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Speaker 1: But I am curious, we decided explicitly not to do a Delphi voting-type session today. And the goal, like we said at the beginning, is not that everybody walks out of here converted, but I'm curious, in the last couple of minutes, and anyone feel free to speak up, what that looks like. Obviously, continued engagement with pathology is critical. I think continued conversation about work with cancer more broadly across the medical community is really important.

But I'm open to comments on next steps.

Speaker 2: Do you want to make any?

Speaker 1: In terms of ISEP and all that, how does that work? I mean, is it something you guys discussed at this?

Speaker 3: Yes. So yeah, that's a good question. I'd like to answer that question. So actually, it's perceived by us in pathology that this idea is dead on arrival. Pathology rejected it completely.

Right now, the vote is like 80 aggregate—the ISEP survey is 80% against and 20% for renaming. But I think what we are not doing at this point that we should be doing is something like this. We should have some explanatory means. We should look into the feasibility of renaming, look at the criteria, see if it's doable or not.

I mean, listening to Mr. Wolinsky earlier, there's a real patient problem. And I think that's where pathologists should be looking—whether this is feasible or not. At this point in time, we have not done that yet.

And then of course, when we vote, if ISEP asks me if I'm in favor of renaming or not, even if I favor renaming, I would say no because what are the alternatives? It has to be laid out.

Because for me, I would consider renaming if there are criteria or if the alternatives are presented. It's not done yet.

And I think as an aside, this will influence us—something like this. They cannot do that. And so this is probably the future direction for us, hopefully.

Speaker 1: We'll all come to ISEP.

Speaker 4: You actually said, even though I'm not a pathologist, I was going to say this is not going to go anywhere unless some group from within the world of pathology brings it to the pathology community. Because for urologists to say to pathologists... I'm just, as an outsider, saying we've got to relabel when it's really so foundational—I just think it's not going to apply. I think it really does have to... There has to be a conversation within that.

And I think that there has to be some kind of reckoning out of your paper—a question of whether you want to keep pursuing this or, based on what we've discussed, take a big-picture view. One thing that's been really good about this afternoon is that things have come up that are not just the clinical question, right?

And I think that when you put all of these considerations together—the pathology discussion, the insurance questions, for example—and you put it all together, then I think it does... You can talk forever about things. But I do think, given the effort that has been put into bringing this group together, that your write-up of this should be a reckoning of whether you guys are going to keep arguing this, or based on the big picture, decide it's really not happening. I think it's not too much to say this write-up should be a reckoning.

Speaker 3: And just to add to that, for the technicalities of a name change, it's really in the purview of pathologists. We are in charge of the WHO classification, no matter how they name it. If it's not going to make it in the WHO, then it's nothing. The WHO— that's what the ICD codes are based on, the registry terminologies are based on. So it really has to go up there. And that's the pathologist's purview.

Speaker 5: Both of the last two comments are absolutely correct. And actually, the leading lights in pathology for prostate, with a lot of help, have consensus statements that have already put their foot down and said, "This is still going to be called cancer." So you guys actually almost have to prove us wrong—us pathologists—to change this. And I think you largely have, but it's got to come from some sort of evidence-based demand that's irrefutable, and that's a high bar. I'm not sure it's an easy thing to do.

It's never been easy to change pathologists' minds, but this one's going to be a tough one.

Speaker 6: I think we could work on it. Sandy's circulating some terms, possibilities.

Speaker 1: You said 20%, do you think five years ago it was less than 20%?

Speaker 3: Well, the 20% is just the survey, right?

Speaker 1: Yeah, right.

Speaker 3: It's hard to change the status quo if we don't know the alternative. If some expert in pathology says, "This is what it is," others will follow. Right, exactly. So we don't know.

I think the point is that we should have a discussion at the society level. What are the alternatives presented? Totally examine it—if it's acceptable or not. And we haven't done that at this point.

Speaker 2: Matt, have you thought about where to go with this? What's going to happen next?

Speaker 1: That's what we're talking about right now. We've thought about it, but of course, we want to see how the data is going to go.

Speaker 2: Can I just say...

Speaker 1: Sorry.

Speaker 2: I would just add an opportunity for clinicians to spend more time at pathology meetings. Ingrid's expressed to me privately and publicly today that there's support and resources from CDC, NCIA. AHRQ has been involved and is willing to support further discussions and conferences like this, and the paper that comes out of it, but it's going to have to be organic.

Speaker 7: I was going to say one of the big things I got is that there are other ways to sort of achieve what we want to achieve, which is less Gleason 6 cancer being treated, anxiety, etc. I was very struck—Jeff Michalski's gone—but just making the NCCN guidelines stop saying "If you have very low-risk prostate cancer, surgery and radiation are a great option" would be a huge win. You know what I mean?

I never understood that, for 20 years, because let's say you have 30 or 40 years—well, then you're on active surveillance for 10, 15, 20 years, and then you get treated—that's still a win.

Speaker 1: That was a great point. You were at this NCCN controversy. It was just last year, right? They took the bird out for three months and then put it back.

Speaker 4: Can I ask a pathologist a question, though? Because I'm wondering, when you talk about evidence, would a very well-done model that combined the best of what we know and showed robustly that there was a way to improve harm-benefit trade-offs if there was a change—not the name, but something—a change that kind of changed the mindset of providers and patients...

Speaker 5: Models and statistics are great.

Speaker 4: Would that be evidence? Would that be—

Speaker 5: But pathologists are empiricists, and we look at one patient at a time. And so actually, I think what needs to happen is a mechanistic understanding of the biology. And we asked several questions that you guys don't have... Well, we don't have answers for, either.

Like, do Gleason 3+3s transition or become sub-clones that are 4s? And I don't think that's a known thing. I think it's unlikely that that happens. I think the 4s that you find are new initiation foci, but it's not proven.

So those are the kinds of things that would convince us—if we did clonality analysis and showed that whenever you had a lot of 3 and then you popped up with some 4, that they're separate. Those kinds of things get pathologists to say, "Okay, that's two different cancers, and I can diagnose one or I can diagnose the other or both."

But we need to be very clear that it's not a Vogelgram progression. And if that's proven to us, then we will distinguish between those two different kinds of cancer. And if one of them turns out not to be cancer by any definition, then we will say that. So that's the kind of evidence that's needed. When I say evidence—but it's a high bar.

Speaker 4: I'm just going to say quickly, because I know Andrew wants to say something, I'll just say that the empiricists who looked at the two large screening trials did not know what to do with themselves, right? They had to go beyond and do some modeling. And so I think this actually calls for—when talking about what's next—maybe a discussion about evidence, and the kinds of evidence that might be brought to bear, and whether there's some combination of evidence, besides the very rigorous standard that you put there, Sandy, that actually might be acceptable to the pathology community.

Speaker 2: So that could mean what Ruth said, but I would pose to you, Sandy—and those are important questions—but if the goal of screening currently is to identify pattern 4, why does it matter if pattern 4 comes from pattern 3? In some individuals, it comes de novo, it comes from high-grade PIN, or it comes from a reason we don't know about clinically—it just doesn't matter. It'd be interesting to answer that fundamentally, but I'm not sure how...

Speaker 5: Yeah, you ask a good and somewhat loaded question, of course, which is I believe that some of the 4 that we see should be grouped with the 3. It's also indolent disease. And what we need are those pure biomarkers of risk that would tell you, "Okay, this is a consequential cancer, and this is not." And we're never going to be 100% on that.

But statistically, and with modeling, I agree, Ruth—this is where we need to go. You need to get to a point where, as we did with breast cancer, in fact in the early days of Oncotype, where we were able to say, "Hey, your risk of dying from your chemotherapy is equal to your risk of dying from your breast cancer. So what kind of person are you? Do you want to have the chemo anyway? Or do you want to just take your chances with the cancer and save yourself the toxicity of chemo?"

And those are those very low percentage risks that patients have to confront, and we have to educate them about.

So I think we need to get there, so that we're actually better informing our patients on how to make these decisions.

Speaker 6: I think something that would... The pathology community would... It would really help us understand just the importance of it, the urgency, the frequency, and severity of the collateral damage—be it from radical prostatectomies or radiation therapy.

I mean, if virtually every patient has problems with continence and impotence, and the severity of that—if we knew that, that could be pretty useful.

Speaker 1: But we know—we already know—that nobody with Gleason 3+3 dies. Period. Sometimes 3+3 is a marker, and we find a higher-grade cancer, and that is reasonable. It actually needs to be treated.

But we know that 3+3 has never, ever been. So how much more empirical evidence do we need? We know that 3+3, in the absence of something else, does not spread, but cancer does.

And again, to a patient—and this comes back to the comments that Laura made, and made multiple times today—to a patient, cancer spreads, cancer kills you, and then it stops. And if it doesn't do that, and we have reams of empirical evidence that Gleason grade Group 1 does not do that... I don't know how much more empirical evidence we need. And we have hundreds of thousands of cases of variants showing that grade Group 1 never acts like a cancer group.

Again, I like this declination analogy. It kind of looks like it on pathology, but it doesn't.

Speaker 2: I've heard all these anecdotes of pattern 3 causing problems, and I still shout it out, and no one has proved me wrong to this point. I'm waiting for the... As I said at the beginning of the meeting, I'm not aware of a single man in human history who's died from contemporarily graded pattern 3, without the evidence, without concomitant presence of higher-grade business.

Speaker 4: But you guys are going back to the argument about the next steps.

Speaker 2: You're absolutely right.

I just have one thing. I responded to the group at the beginning. The goal of the day was healthy discussion, but it's been superseded, and I want to give a huge thanks to everyone for their thoughtful comments and for being focused and dedicated. So thanks.