Drs. M. Scott Lucia, E. David Crawford, Gerald L. Andriole, Stacy Loeb, and Omer Kucuk presented at the 26th International Prostate Cancer Update on Thursday, January 21, 2016 on “Prevention, Screening, and Genomic Markers Panel Discussion.”
Keywords: prostate cancer, genomic markers, PHI, PSA
How to cite: Lucia, M. Scott, et al. “Prevention, Screening, and Genomic Markers Discussion.” Grand Rounds in Urology. January 21, 2016. Oct 2020. https://grandroundsinurology.com/prostate-cancer-m-scott-lucia-et-al-prevention-screening-genomic-markers-discussion/.
Prevention, Screening, and Genomic Markers Discussion – Edited Transcript
M. SCOTT LUCIA: We’ve got questions that have come up. So we’ll start with you, Stacy. You have published that you feel that PHI [the Prostate Health Index] is superior to PCA3 [prostate cancer antigen 3]. Do you think 4Kscore is better or worse than PHI for suggesting a need for biopsy?
STACY L. LOEB: So that’s an excellent question and actually there’s one head-to-head study that show that they have similar performance for biopsy outcomes. So I think PHI and 4Kscore are both excellent choices that have been endorsed by the NCCN [National Comprehensive Cancer Network] Guidelines to make a biopsy decision. I guess one difference is that PHI has also been shown in a serial fashion for men with prostate cancer on active surveillance. That’s another domain where it has been tested at Hopkins and in Japan. But hopefully we’ll have some more data soon from 4K for men with cancer undergoing active surveillance. I think both are great choices and both are more associated with clinically significant disease than PCA3.
LUCIA: So why is the PHI test not being marketed? Could one add DRE [digital rectal exam] and prior biopsy and get similar results to 4K?
LOEB: Yeah, I mean I can’t answer about the marketing. I don’t have any kind of ties with the company, so I have no response. I guess you could ask Beckman Coulter about the strategy. Could you add the other test? Yeah, absolutely. The Rotterdam Risk App actually does that. So, if you go to the App store and get the Rotterdam Risk App, you can put in the PHI test and the DRE and the other stuff and use it as part of multivariable risk stratification. And they show that using PHI as part of one of these multivariable prediction tools improves its performance. So absolutely, I think multivariable risk stratification is the way forward and it can be done either with 4K in itself or with PHI along with these other factors.
LUCIA: Should we alter or change the PSA density cutoff with the use of multiparametric MRI?
LOEB: I don’t think so. I mean, I think there’s a lot of good data behind the 0.15 cutoff. That’s what’s been used in the Johns Hopkins active surveillance program. And you know, it’s very interesting because PRIAS, the [Prostate Cancer Research] International Active Surveillance program, uses a PSA density of 0.2 instead of 0.15, and that doesn’t sound like it would be such a huge difference, but there is actually quite a difference even just within that little range there. So PSA density is probably an underutilized tool, and I think it’s nice that now that we’re doing more imaging maybe it can make a comeback.
LUCIA: So what’s the relative cost of say PHI, 4K, and PCA3?
LOEB: I mean that’s a real tough question and a moving target. I proposed at a previous meeting that I think the best innovation that someone could make would be an app where you put in the patients’ insurance and the tests that they want and then find out how much they have to pay for it. So, yeah, I don’t know. I mean, in all different places these things have different tests, and whether the patient is going to have to pay any of it at all has changed over time, so I can’t really answer that. I don’t know if anyone else can.
LUCIA: Dr. Crawford, you showed the different buckets for use of the different biomarkers. Could you comment on which biomarkers you presently use in each one of those buckets?
E. DAVID CRAWFORD: Oh, that’s going to get me in a lot of trouble, isn’t it? Who’s in the room now?
LUCIA: All of the above.
CRAWFORD: First of all, to answer the question that Stacy didn’t answer about cost, the biomarker flow diagram grid we have actually has that information. It’s changing. As you said, it’s a volatile target that is changing. Regarding bucket one, who to biopsy, you know I’ve already laid my cards out – it’s PSA, that’s first. And then, if it’s greater than 1.5, right now we’re doing a number of markers, but we’re doing 4Kscore. Primarily because it was one of the first [tests] that helps us direct toward diagnosing high-grade cancers, which is Gleason pattern 4. There are other ones that are out there that deserve evaluation, and you just talked about PHI. I think PHI’s a great test, and when it’s hooked up with DRE and prior biopsy may be good. It has not been well-marketed. PCA3 is not approved in that arena, although we did a nice little study of it with David Boswick with 1,900 people and so did the work. So right now it’s 4K. Who to re-biopsy? I think there are very strong data that exist for ConfirmMDx and that’s what I use. There are other people that are nibbling at it. PCA3 has an approval. Again, I don’t think the data are strong. The same thing with 4Kscore. I asked Jay Newmark to provide me with some information and he did. It’s helpful but it’s still not that comparison [with] everything else that exists with some of the other things. So then, who to treat? Both of the tests – the Oncotype DX and the Prolaris – give you different information, and it depends on what turns people on and physicians. We actually have an abstract we submitted to the AUA [American Urological Association] where we’ve done both on people, and probably have 35 or 40 patients who have done both tests, and when that comes out we’ll let you know.
LOEB: Yeah, that’s actually a really good point that you just made. As part of my grant on active surveillance, I’ve been doing qualitative interviews with physicians around the country of different types doing active surveillance. And they have brought up that, and [that] some people prefer the report to say what is the ten-year risk of prostate cancer mortality with conservative management, which is what Prolaris reports give you. And then others feel that the Oncotype report telling the risk of finding adverse pathology at prostatectomy is more helpful for them to inform patients in that particular clinical decision point. So I don’t think it receives as much recognition about how the information and what you would tell the patient is very different between those tests.
CRAWFORD: The other thing is, I can tell you, with talking to patients, they actually like both. You know, that’s another piece of information, and if you look at melanoma and a lot of other cancers, we’re doing multiple markers. We’re not even talking about that in this disease and it does make sense.
LUCIA: So here’s a question that really can go to both Gerry and Matt and [we can] see how you each answer this. How many of the 27% of men who have a screening PSA above 1.5 ultimately have a prostate cancer requiring intervention? 27% still seems like a lot of men to further investigate.
GERALD L. ANDRIOLE: I don’t think we know the answer to that. Where is Matt? That was his study.
CRAWFORD: That’s in my thing. You take PSAs of 1.5 and a screening population. 30% of men will have a PSA of greater than 1.5, and they deserve evaluation, not intervention.
LOEB: Yeah, that doesn’t mean suggesting biopsy. You’re just suggesting [that] those are the ones that you even have a shared decision-making discussion [with].
LOEB: And so that you don’t have to do this long discussion with absolutely everybody.
ANDRIOLE: Yeah but at a very high level? Only 3% of men are going to die of prostate cancer. You have already found 27%, so it’s a 9-to-1 ratio, but really there’s some men who have very low PSAs who are in fact going to die of prostate cancer because they developed their tumors later on.
CRAWFORD: Life is not perfect.
ANDRIOLE: So you’re not going to get them all. So still you’re going to find many more cases and evaluate many more people and they may not be the right people.
CRAWFORD: Well, you’ve got to start somewhere.
ANDRIOLE: I agree with you there.
CRAWFORD: You know, it’s the proverbial argument. I said at this meeting 15 years ago, at age 50 every man should have a prostate biopsy, and people laughed at that.
ANDRIOLE: Well, you maybe have an MRI?
CRAWFORD: Ah come on, not the MRI stuff.
ANDRIOLE: Now, before you get too much BPH [benign prostatic hyperplasia]…
CRAWFORD: I’m not buying that stuff.
ANDRIOLE: Too much BPH, David. You don’t know because you probably don’t have BPH.
CRAWFORD: But you know.
ANDRIOLE: The adenoma, you know, it changes the shape of the peripheral zone…
CRAWFORD: Maybe in the hands of a few people, like the folks at NYU [New York University].
ANDRIOLE: I’m not recommending it, and it may not be MRI alone.
CRAWFORD: And certainly not.
ANDRIOLE: It could be MRI PET.
CRAWFORD: Well maybe some other, there’s a lot of other. We’re not going to be doing what we’re doing or talking about [what we’re talking about] right now five years from now or ten years from now. I guarantee. There are companies out there that have ways to attack prostate cells immunologically that are probably going to replace radical prostatectomy.
ANDRIOLE: You know, you just wonder how reassuring is a negative biopsy?
CRAWFORD: It’s not. How reassuring is a negative MRI or a positive MRI?
ANDRIOLE: Well, I don’t know which is worse or which is better.
CRAWFORD: If you look at PINA’s data, 30% of that time they’re missing bad cancers. Is that acceptable?
ANDRIOLE: No. No test is perfect, but the volume or the amount of cancer that’s missed… I’m not a big advocate for MRI. I’m just saying if you had to do one thing…
CRAWFORD: You sounded like you were.
ANDRIOLE: No, but I’m playing the devil’s advocate. If you had to do one thing would it not be a non-invasive thing? Rather than an invasive one?
CRAWFORD: How would that flow in your mind? How would that work?
ANDRIOLE: Well, if you had… If you were at risk…
CRAWFORD: The Andriole workup. So, okay, a guy comes to you.
ANDRIOLE: If you were at risk… If you were at risk because of your PSA.
CRAWFORD: I’m a man, I’m at risk.
ANDRIOLE: Yeah, no, I understand that, but we wanted to see if you were at high risk.
CRAWFORD: And what makes me at high risk?
ANDRIOLE: Your PSA, your 4K, your PHI…
CRAWFORD: What level? What level?
ANDRIOLE: I have no idea, David.
CRAWFORD: Well you just told me less than one, you still can have cancer. Come on. You can’t have it both ways.
ANDRIOLE: You can and then we’re going to get…
CRAWFORD: But I want to know. I’m a patient talking to you. I walk in, ‘Dr. Andriole should I get PSA? Okay… Do you want to draw a PSA on me?’
ANDRIOLE: How old are you?
CRAWFORD: I’m not telling you. Older than you.
ANDRIOLE: Yeah, I want to get a PSA.
CRAWFORD: Okay let’s say I’m in my 60s.
ANDRIOLE: A PSA is information. I agree with you.
CRAWFORD: Okay, so you’re going to draw… You’re going to think, I get a PSA?
ANDRIOLE: Yeah, I think every man should get a PSA.
CRAWFORD: Okay, it comes back 1.51.
ANDRIOLE: Yeah, I would say if you’re 40 years old and you don’t have…
CRAWFORD: I’m not 40. I’m 60.
ANDRIOLE: Well, do you have a big prostate? I need more information.
CRAWFORD: I don’t know if I have big prostate. Tell me.
ANDRIOLE: Well, I can find out.
ANDRIOLE: I can get an MRI.
CRAWFORD: You’re going to get an MRI? I’m claustrophobic, man. I’ve had two MRIs and I hate them.
ANDRIOLE: All right. I can stick my finger up your rear end and estimate your prostate.
CRAWFORD: You can do that. Okay. The problem is I have hemorrhoids and it hurts, okay.
CRAWFORD: But you do it and my prostate is moderate.
ANDRIOLE: Is what?
LUCIA: He said moderate.
CRAWFORD: Moderate size.
ANDRIOLE: Moderate size. What does that mean?
CRAWFORD: Oh I don’t know. You just told me that.
ANDRIOLE: I would put you at a number, I would say it’s 50 gms, 40 gms.
CRAWFORD: And you’re that good?
ANDRIOLE: I am, I got to tell you. No, I don’t know.
CRAWFORD: Well, what did the PLCO [Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial] data tell us about looking at DRE sizes?
ANDRIOLE: Well, the nurses… The nurses weren’t very good…
CRAWFORD: Nothing! Who was the PLCO PI [principal investigator] for prostate? Who was the PI? It was you!
ANDRIOLE: Who was the subordinate PI? Who got to be the first author on the only positive paper that came out of the damn thing?
LUCIA: So let’s change. What if we take the dynamic of looking at the patient who’s got a PSA for the first time? He comes into you with a 1.49 PSA. Let’s say he’s 62 years old and he’s got a 1.49 PSA? First time he’s ever had a PSA.
LUCIA: What are you going to do with that? How hard and rigid are we on these PSA rules?
ANDRIOLE: I’m going to…
LUCIA: We used to be hard and rigid at 4, weren’t we? And then we became hard and rigid at 2.5, and now we’re saying 1.5. How rigid are we on this?
ANDRIOLE: No, that’s a relatively high PSA. He should be followed. He could have a rectal exam and just have his PSA monitored.
LUCIA: How often?
ANDRIOLE: He could get a reflex test if he wanted.
LUCIA: And if he’s 49?
ANDRIOLE: Well, then it’s really alarming, and this could be the guy that you would choose to get an MRI.
LUCIA: So now we’re going back to be devil’s advocate here. We’re going back to what Dr. Rosenberg said. We’re confusing people now. Because now you’re talking about age-related phenomenon. If we’re trying to make it simple for the general practitioners, that’s not a simple answer.
ANDRIOLE: No, but you’re talking to me. I’m a urologist. If you want to give a different message to the urologists, than I think you should. Family doctors can have a different message, a simpler one. Because, like you say, they have 40,000 other things they’re thinking about when they see a patient. So yeah, that 1.5 is a great cut point for a family doctor, but when that patient then comes to me as the urologist, I don’t think it can be that simple.
LUCIA: It’s a pretty good answer, but you have the same patient. First time, 1.49, 62 years old?
ANDRIOLE: Well, that to me is close enough given all the vagaries of different PSA assays and all the confounding things that can raise it up.
CRAWFORD: Close enough to the low or close enough to the high?
ANDRIOLE: Close enough to the high.
CRAWFORD: I can’t believe that people are going to MRIs rather than biopsies.
LUCIA: Larry Karsh, in the back, he wants to…
LARRY KARSH: Okay, so I get these tests. I’m getting the PHI, I’m doing the OPKO 4K, and actually when my patient comes in I have my scribe sit down and he puts in the PCPT [Prostate Cancer Prevention Trial] calculation in the risk calculator. And, you know, what is the number that moves the needle for you on who to get a biopsy on? Let’s say you have a 9%. What would you tell the patient? You have a 9% risk of having a high-grade cancer?
CRAWFORD: I’d biopsy him.
ANDRIOLE: Yeah, I think most people pull it at 5% or so.
LUCIA: Yeah, why not?
DR ANDRIOLE: Or do an audience response. Can you quickly type one up?
CRAWFORD: What does the audience response say?
LUCIA: We’ve got to define it in a way…
ANDRIOLE: Well, just say, “No matter how you got there, what probability of prostate cancer do you think warrants a biopsy in a very healthy man?”
LUCIA: Okay, so the question is going to be, “At what level of risk do you decide to proceed with a prostate cancer biopsy?”
ANDRIOLE: In a very healthy man.
LUCIA: Let’s add some categories here: 5%, 10%, 20%, or greater than 20%.
ANDRIOLE: Or you could even go lower.
CRAWFORD: I would have gone lower. I would say 5.
LUCIA: How about less than 5, 5, 10, 20, and greater than 20? Five answers.
CRAWFORD: All right, let’s talk about something else while he does that.
LUCIA: There’s a question here: Is transabdominal ultrasound sufficient to accurately calculate PSA density? How do you feel about that?
CRAWFORD: We need to talk to the ultra-stenographer, but I don’t think it is. MRI is, but not transrectal ultrasound.
LUCIA: But that’s how it was defined to begin with.
CRAWFORD: I mean, transabdominals… That’s what they usually do when they do renals. They look at bladder volume and also thickness and also look at the prostate, and they’ll comment “prostate is large.” Is that right, Phil? Are you a radiologist still?
PHILLIP J. KOO: So, I don’t do a ton of ultrasound but transabdominally getting an accurate prostate volume to me sounds like it’s a little bit of a stretch. I believe if you were going to try to get a volume an endorectal type of exam would be much better. The MRI obviously makes a lot of sense as well, but it’s more expensive and takes a lot more time.
LOEB: I mean, even TRUS [transrectal ultrasound] isn’t perfect. We compared the digital rectal estimates and the TRUS estimates to prostatectomy specimens, and the correlation is about 0.4 for the digital exam and 0.6 for the TRUS to the prostatectomy specimen weight. But the thing is, you don’t need an exact number. So that’s the thing. I mean if you say it’s 50 and it’s really 62, you know, that’s a big difference. Then, if you said it was 10 and it’s 75, so for the ERSPC [European Randomized Screening for Prostate Cancer] risk calculator, which is what I was discussing earlier, it’s not that they say that you should make an exact estimate with the DRE, because you can’t. What they’re saying is that if you estimate that it’s small, medium, or large that that alone adds information to a risk calculator tool without even assigning a precise number.
LUCIA: What are our answers? Well, overwhelmingly… We only had three votes and all three of them went for 10%!
CRAWFORD: Maybe we didn’t word it right. 5 to 10, less than 5, something like that.
ANDRIOLE: Is Larry Karsh’s 9% enough for you to do the biopsy? Is that close enough for you?
CRAWFORD: Well it’s close enough according to you.
ANDRIOLE: Yeah it would be for me. I would have drawn the line at about 5.
CRAWFORD: Yeah I would have too. I would look at the patient’s age and everything else, you know.
AUDIENCE: We heard that the urologists aren’t quite ready to accept a change in PSA and the family practitioners have to be taught about it. Where do the pathologists stand about incorporating the 2005 and 2014 guidelines?
ANDRIOLE: Actually, that one particular issue has been well-received in terms of changing the prognostic grade grouping because we really didn’t make a modification to the Gleason grading system per se. We’re just using it smarter. So it’s been well-received. I don’t have a recommendation on positive margins. The data seems to indicate that the greater the tumor, the positive margin makes more of an impact rather than having an a positive margin per se.
LUCIA: Isn’t there a standardized report that you guys do?
CRAWFORD: Yeah they don’t do it.
LUCIA: It’s mostly not done.
ANDRIOLE: Our guys do it.
CRAWFORD: Yeah ours do.
MAKI: Rich Maki from Cleveland Clinic Florida. The risk factor that would trigger our recommendation for a biopsy is really only half the equation, because you can have a patient with a exactly the same parameters and patients are willing to accept higher or lower risk. So that’s the part of the shared decision-making and you really have to discuss that with the patient.
LUCIA: Good comment.
AUDIENCE: So the part that’s missing from this is some kind of… I’m going back to the discussion about what percent should drive the decision to do a biopsy. What I tell patients is, would you be happy if your risk was the same as someone who wouldn’t come to see me? Right, so in other words, if his risk of having cancer found is no different than someone with whatever the normal PSA threshold, you want to use is. Well then, it’s reasonable that you don’t get a biopsy. So if you can reduce someone’s risk by testing them, and you can get them to the same risk as if their PSA was 1.5, that’s probably good enough, right? So whatever you use as your PSA cutoff, think about what that risk for having cancer, what that risk for high grade cancer is, and use that as a cutoff. It’s rational. You create an anchor.
LUCIA: One more question.
AUDIENCE: In our area, Dallas Fort Worth, none of these new markers are covered by insurance, so we can’t get the pathologists to do them. And therefore, it’s kind of a moot point here, for if they’re not covered and the patients aren’t going to pay cash for them… They are kind of expensive, [so] what’s the use of discussing these things until they get covered? They are not covered. I don’t know if it’s that way around the United States or not, but in our area that’s the situation. Are they covered by Medicare anywhere?
ÖMER KÜÇÜK: If I throw one comment in, the thing to do is to avoid over treatment. So one of the considerations would be, if the patient is willing to accept active surveillance, there is more of a chance that he will be diagnosed with non-significant prostate cancer. And that has to go into the consideration of whether to go for biopsy or not.
LUCIA: We’re probably going to have to shut this down. So, thank you for your input. Thank you for the questions. Thank you panelists and for everything this morning.