Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist. We are in Cartagena, Colombia for the SCU 2025 annual meeting. We're delighted to be joined by Dr. Nicolás Villarreal and Dr. Matt Cooperberg, both who discuss the debate of whether we should be calling Gleason Grade Group 1 prostate cancer. Gentlemen, it's great to be here. Thanks for joining us on UroToday.

Nicolás Villareal Trujillo: Thank you for inviting me.

Zachary Klaassen: So Nicolás, let me know why are we having this debate in 2025? Gleason grade Group 1 cancer, no cancer? What was the premise for the debate?

Nicolás Villareal Trujillo: So what happened is when the prostate cancer screening started and the PSA era started, we had a lot of diagnosis and a lot of incidents arising in the incidents of prostate cancer. And what we have been looking after that, afterwards is that the mortality hasn't gone down as it should be.

Zachary Klaassen: Sure.

Nicolás Villareal Trujillo: So maybe we are diagnosing a cancer that is not really a cancer and maybe we should not do some treatment in those patients. That's why active surveillance started and now it started and right now is the standard of care in the grade group patients.

So, even though we are doing it, some people are saying, why don't we change the name of this pathology to a non-cancerous lesion like we have been doing something different or let's say Gleason 2+2, we now know that's not cancer.

So, maybe it's time to change the name of Grade Group 1 to a non-cancerous lesion.

Zachary Klaassen: Excellent. And Matt, you took the argument for not calling it a cancer and we're big active surveillance guys. I know your CV has a ton of active surveillance papers in it. Tell us why we should maybe be de-escalating that term for Grade Group 1.

Matthew Cooperberg: Well, because the story really predates even the screening era by 2,000 years. The word "Cancer" literally goes back to Hippocrates, and has this incredibly deep cultural resonance for literally millennia as a diagnosis that kills you, right?

This has an incredibly deep-rooted history in the psyche of Western medicine and people. And for literally thousands of years, this was a diagnosis that meant spread and death.

Zachary Klaassen: Right, right.

Matthew Cooperberg: For maybe now 150 years, we have been defining cancer based on what it looks like under the microscope. And that obviously has led to fantastic advances in our understanding of the disease, the way we classify cancers and the way we manage it.

Now in the last couple decades that we have been screening, we are taking tissue that is causing no symptoms, sending it to the pathologist and they say, "Well this looks like the thing you sent me 20 years ago that was killing the patient," and we're still using the word "Cancer."

So it is not by intention, but really by an accidental evolution of history that we have converted cancer from a clinical diagnosis to a pathologic diagnosis. This was not, again, an intentional shift. It has just sort of happened over time.

And of course as we got into the screening era, as my colleague says, we have started to realize we are over-diagnosing and active surveillance has been on the map from an academic standpoint, I would say for 25 years. It is gradually growing in community practice, but we still have a long way to go. There's still a lot of over-treatment and even when we do active surveillance, there are still implications for the diagnosis. It causes a lot of anxiety. There are financial implications in the US, and I'm sure in other places in terms of insurance costs, etc.

There is a paper about suicide rates after diagnosis from Scandinavia, recently. So the word has not lost its significance, even as we have been arguing for, and promoting active surveillance.

And the other piece of it is that we're learning that the switch point at which this is really something different does not really correspond with when the cells start to look funny under the microscope. There are pre-malignant changes that we can identify at the molecular level in tissue that looks absolutely normal, and we actually see more changes in some studies between normal and normal, than we do between normal-adjacent to the cancer and the low-grade cancer.

So, defining cancer based on when the cells happen to lose a layer of cells in the glands, we have to admit that's an arbitrary point in a continuous evolution.

Zachary Klaassen: Yeah.

Matthew Cooperberg: And the argument for a name change is why don't we just push that one step to the right. If we find these glands without a basal layer, nobody would call that normal. Patients would absolutely need to do surveillance. We would need to track them very carefully because some of them have been under-sampled, some of them we will eventually find higher grade cancer that we will need to treat. But in the meantime, for the very many men that don't have that progression, they do not need to carry this cancer label around.

Zachary Klaassen: Yeah, pretty strong argument. What say you, Nicolás? Why should we still call it cancer but, still do active surveillance?

Nicolás Villareal Trujillo: Yeah. So I had the against part, and I agree with Matt with most of what he's saying. And in theory he's right.

But there's something that happens in the US, something that happens in the reference centers that you have all the tools to do a right diagnosis. You have rural pathologists, you have MRI for every patient, you have biomarkers, you have genetics, you have Decipher score and all of this things that you can use to rightly point what you have is not a Grade Group 2, 2, or 3 or 4, and is actually Grade Group 1.

Zachary Klaassen: Right.

Nicolás Villareal Trujillo: What happens in the community where it is treated the most amount of patients, what happens outside the US, and in the practice of the rest of the countries is that we don't have all that tools.

I have MRI, I have the Decipher score, I don't have genomics and I don't have all the biomarkers that I should have.

And what happens in the real practice is most of the patients, let's say more than 50% of the pathologists are not trained to do a right diagnosis. So when I receive Grade Group 1, I have the means to do a revision from a uropathologist and in the 50% of the cases is going to change.

But not all the urologists have this means. So they're going to have to stick with what they have. So, they're treating patients with let's say a bad pathology and they're not going to know that it's really a Grade Group 1. So the implications not only here but in the world, is that we're going to under-diagnose patients with higher scores cancers and with a more aggressive disease. So I think maybe we are not ready to do it in the whole world.

Zachary Klaassen: Yeah.

Nicolás Villareal Trujillo: Maybe in a reference center you can do it, but in the world it's not that easy. Sure. And the other thing is active surveillance I think is a growing treatment. I know it's a standard of care. I do active surveillance, but the percentage of patients lost during active surveillance can change between different papers, but in different health systems, in different countries.

I presented a paper that said that 10% two years are going to get lost. And that's in the US. In the rest of the countries it may be higher. So you have a patient that you don't have the accurate diagnosis of Grade Group 1 and you enroll it in active surveillance. It may be lost during the follow-up in the active surveillance.

So I think we maybe not be ready. I agree. And when we have the whole world covered with good pathology with MRI, I think maybe in genomics, maybe we are ready to change the name.

Zachary Klaassen: Yeah, great argument again as well. Fantastic. I want to ask both of you as we sit here in 2025, Gleason Grade Group 1, low volume prostate cancer, regardless of how we say prostate cancer, no prostate cancer. How should we be counseling our patients? Maybe we'll talk to Matt.

Matthew Cooperberg: I have started telling patients we shouldn't call this cancer. I think Scott Eggener tells them this is the wimpiest form of cancer, but those are patients that have made their way to academic practice. That's right. And part of the problem is there's still lots of patients even around the cities, we don't have to get too far into the hinterlands to find urologists that are still recommending treatment for high volume 3+3 or even low volume 3+3 based on spurious arguments about risk of under-diagnosis, this, that and the other thing.

So when you get out of the academic centers and frankly even in some academic centers in the US, there is still a lot of variability. So these days we are really tailoring surveillance, the patients that have low volume 3+3, we do a confirmatory test, find the same thing. We are really trying to back off even more to find patients we can really slide toward more of a watchful waiting-type paradigm, and intensify surveillance, on the other hand, for patients that are borderline, that have aggressive genomics, that have high volume disease, BRCA mutations, strong family history, things like that. But the counseling piece, the other half of the counseling piece though, is before the diagnosis itself, which is the screening question.

And this is one of the reasons we've really been pushing for this concept of name change is that at least in the US 90-plus percent of the screening, probably 98% of the screening happens in primary care, not in urology practice.

And I totally agree, there is a non-zero number of men that may die because we change the name and they don't take surveillance seriously and they disappear. But that number would be absolutely dwarfed by the number of lives we would save, if we can get every man a screening PSA test between 45 and 55.

Zachary Klaassen: Well said.

Matthew Cooperberg: And the only way to do that is to convince our colleagues in primary care that over-diagnosis is over. So from the counseling standpoint, the counseling at active surveillance has become frankly pretty straightforward in our center, and a lot of other places. I think the complexity is our counseling to our colleagues in primary care, honestly, about what surveillance means, about what this diagnosis means.

Zachary Klaassen: Yeah. Great points. Nicolas, how about you? Counseling patients? Gleason Grade Group 1 low volume disease?

Nicolás Villareal Trujillo: Yes. So I have two types of patients. The first one, they educated patients and the second one, they're not that educated.

Zachary Klaassen: We have those patients, too.

Nicolás Villareal Trujillo: Okay. So the second ones, they're going to say, me, "Doctor, tell me what should I do?" And I tell them, "You are going to have active surveillance." They say, "Okay, I'm going to do whatever you say."

So I try to explain, but at the end, in the middle of the conversation, I realized he's going to do exactly what I'm going to tell him. So I tell him, "This is the best thing we can get. Active surveillance is the standard of care. There's nothing going to happen if you follow up with the active surveillance."

In the diagnosis set. I don't do diagnosis. I work in a reference center and most of my patients are from urologist and they do the diagnosis and the primary care patients. So, when they come here and they have a low-grade Grade Group 1 prostate cancer, I do an MRI. I try to check up with the pathology to see is really a Grade Group 1. And then I tell them they have a cancer. And I do a little example. You can have a dog in your house, but you can have a pit bull or you can have a, I don't know, schnauzer. They're both dogs, but they're different. This one's really aggressive. He could kill you, and this one he can bark, but that's it.

So that's like a real example that I told him.

Zachary Klaassen: I like it.

Nicolás Villareal Trujillo: So, you have this dog, so we are going to follow up you and we are going to try to know if it's really this dog or it's going to change in time or I was mistaken that you have something in the middle and then we're going to do treatment.

If I, in the time, I realize it's not this one, we are not going to lose anything. You're going to be cured in the same amount if I do it right away.
And some of the patients, they're really stressed out with the word cancer. So they're telling me, "Doctor, I'm not, I may be wanting some treatment."
And then I said, "Okay, we can do treatment, but these are the complications that you can get with treatment. You can have incontinence, you can have erectile dysfunction, you can have radiation cystitis, proctitis and all of that thing."

And when I tell them that, they say, "No, I'm going to go with active surveillance."

And almost I would say 99% of the patients actually do the active surveillance set of the treatment.

Zachary Klaassen: Yeah. I think to put a bow on this great discussion is it's all about the counseling the patients, what this really is, what this really means. Any quick take-home messages for our listeners today?

Matthew Cooperberg: I think this is a conversation which is gaining momentum, which is pretty exciting to see. It's been percolating for a long time. Oliver Sartor wrote a paper in 2006. There was a JAMA article from Laura Esserman, and Ian Thompson in '08. But it's really, I think in the last few years that we're really seeing more serious engagement.

There was just a white paper from ISIP and GUPS, the two big international uropathology societies in European urology taking on this issue. Not that they were roundly endorsing a change in nomenclature, but at least addressing this question of indolence from the pathologist's perspective, I think with advent of AI and standardization of pathology and standardization of biopsy, some of these concerns about under-diagnosis may start to fade. And I think we're on the right side of history.

Zachary Klaassen: I think so.

Matthew Cooperberg: I think it'll take time, and this is probably going to take quite a bit of time because it is such a highly prevalent diagnosis. Thyroid cancer went down this path a few years ago, but it was a much smaller subset of thyroid cancers that have now been undiagnosed as cancer. So I actually truly think we will get there at some point.

Zachary Klaassen: That's great. Last words, Nicolás.

Nicolás Villareal Trujillo: I agree we are going to get there, but we are not ready yet.

When we do a really change in the screening, how do we do screening when everyone has the tools of doing an MRI before a biopsy, when everyone has genomics, when everyone has the primary care doctor trained to know when not to do a biopsy.

When we have AI and everyone has access to AI pathology, maybe pathologists may be helping themselves with AI, maybe then we're going to diagnose a subset of patients of... No, a subset of Grade Group 1 that is almost 90%, something like that, that is not really cancer, that is going to be an end of this disease. And we may be able to say, this is not cancer, and you can do... Not even do active surveillance, maybe we're going to be able to say "You don't have anything. You're going to be less, a regular patient doing your screening like everyone else."

Zachary Klaassen: Wonderful. Gentlemen, great debate. Thanks for recreating it on UroToday. Thanks for joining us.

Matthew Cooperberg: Thanks for having us.

Nicolás Villareal Trujillo: Thank you for the invitation.