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Speaker 1: All right. One or two questions?

Speaker 2: Pattern four consists of a couple of different types. The four-way form glands are one of the categories, but then the question is, how do you distinguish those from pattern three cancer?

And are they not even the same?

There's some evidence they're the same. The type of pattern four I think we should really keep track of is the cribriform variant. There is a recent meta-analysis publication of some 31 papers that all show an increased hazard ratio with cribriform, of any size, in the prostate biopsy. So, they left unanswered some questions, like the extent of cribriform, but I really think we should record whether or not there's cribriform as the pattern four, or not.

Speaker 1: Is it a fair statement, to all the fellows here, that all of this discussion about the vagaries between calling three/three versus three/four and the potential upgrading that we will see if we change the name from three/three to three/four subtype. We're not going to confuse three/three with cribriform. Is that a fair statement?

Speaker 2: I think so. There are going to be some nuances there. There are other pattern four, the fused glands. I'm not sure what that is. But, yeah, I would really make that distinction. And we don't have good data, except for a large series of patients, sub-categorizing the pattern fours.

Speaker 1: Is there consistency enough in the pathology world in identifying the expanse of the large cribriforms, versus the smaller cribriforms? How much does that matter?

Speaker 2: Yeah, there's evidence it does.

Speaker 3: Yeah, it does better. It has better, more consistency than the other grade four patterns. So, it's one of the better ones, actually. Yeah.

Speaker 1: Is it called consistently, do you think, in the community?

Speaker 2: There's some variance. But there's always a little bit.

Speaker 4: We're working on it.

Speaker 3: Yeah. The only study for interim server variability is by means that's poorly getting poorly differentiated and poorly patterned, poorly formed glands.

Speaker 5: I think it's a great suggestion. Stop calling pattern four, stop calling any pattern three, and you just call cribriform in the bump. I'm being a little bit facetious, but you sort out huge amounts of overtreatment. Huge amounts of it, and it makes your job updating the screening guide, it's very easy.

Speaker 6: We had a quick question-

Laura and I were chatting. If you go back, and for the pathologists in the room, when we changed the Gleason scoring, we got rid of ones and twos, was everything just pushed up to three like we were told? Or were there true entities that were called Gleason grade two cancer that then didn't get called?

Speaker 2: Perspectively I think the ones and twos were really adenosines, or growths that really couldn't be better characterized because we didn't have the immunostains. I mean, you talked to some of the people involved in those first VA studies and they just didn't have them.

Gleason, in fact, anecdotally made the comment that sometimes he'd get these biopsies in consultation. He'd say, "Well, I didn't want the guy sending me the case to feel as though he'd really over diagnosed it, so I called it a Gleason pattern four, or score two."

Speaker 6: But it was cancer. It was called adenocarcinoma Gleason score two?

Speaker 2: Well, he would've. But it wasn't in retrospect because there was a basal cell layer.

Speaker 6: Correct. Right?

Speaker 3: He did not have the benefit of immunohistochemistry at that time. And after the technology, well, we know that these RP9s are mostly adenosis.

Speaker 1: Last question.

Speaker 6: Just to try and integrate some of this, we have the volume issue. We have the imaging issue that Carolyn alluded to. Image-negative cancers are clearly more indolent. There's a lot of data on that. We have the molecular characterization. Maybe what we're talking about is a kind of risk stratification approach, where if it takes in multiple parameters: histology, PSA density, image, yes or no, et cetera, et cetera, and we can identify a subgroup that we would say, "We're not going to call this cancer anymore." But that's a lot different than what we're really talking about, which is saying grade group one, we're going to change the wording.

Speaker 7: For that to happen, we do need a new name for a histologic entity that you call on the biopsy, right?

Speaker 3: It should not be all or none, DG1 cancer or no cancer. It should be criteria-based because of the complexities. That's why you know pathology.

Speaker 8: Don't we already have that with low risk and very low risk prostate cancer? Essentially-

Speaker 3: That's the other cancer-

Speaker 8: ... that doesn't integrate MRI, but it integrates some of the stuff.

Speaker 7: Very low risk doesn't exist. At least we have not identified one in two years, because we don't biopsy. We'll see something in an MRI or a biomarker deposit.

Speaker 11: Samson wants to say something. Can you let Samson say something?

Speaker 3: Prostate cancer.

Speaker 1: Sorry, go ahead. Sorry.

Speaker 2: You are muted.

Speaker 9: Sorry, I think what Adam just mentioned, low risk and very low risk, there's some volumetric considerations there from the pathology perspective.

So, one way to frame this aligned with what Dr. Klotz said, is, so what type of Gleason score six would we be willing to convey to a patient is not cancer, right? And then the potential growing laundry lists of markers from imaging to NGS to BRCA to PTEN, how much are we going to do to convince?

I don't know who it was in the room who said this is a US type of issue because we bend towards treatment, right? Andrew brought up, we'll find one factor and we'll say we can't do it. I think these are real considerations, because I think there are a lot of urologists and a lot of pathologists who would say, "You know, we got to heap on a bunch of markers, of all types, before we feel convinced that you have the truly indolent."

Speaker 7: But Samson, we're making it too complicated. All patterns-

Speaker 9: I agree. I agree.

Speaker 7: ... cannot cause harm to patient. We're talking about every anecdote of badness on active surveillance.

I had a patient where this happened. They had undiagnosed high-grade cancer in there, that wasn't picked up. So, we have to improve our diagnostic capabilities to find those when we're screening them or when they're on surveillance.

But, I'm confused why we're trying to make it more complicated. The molecular stuff is super important, but let's remember, 15% of high-grade PTEN abnormalities, and there's no one shouting that we need to call it cancer because there's a PTEN abnormality.

Speaker 1: Right.

Speaker 9: Just to clarify, I was not arguing that we should do all these things. I was saying it could end up in a place where somebody would feel the need to do a laundry list. I'm not arguing that we should.

Speaker 5: I agree with Scott. I mean, who's our number one pathologist? With all due respect, Samson, it's Epstein, and he says, you need to have pattern four or five to metastasize. That's it. That's the end of the story.

If the word cancer means harm, it means metastasis, and our best pathologist says that pattern three can't metastasize. Therefore-

Speaker 9: In a cohort.

Speaker 7: I can't resist. Dr. Epstein would not say that.

Speaker 5: He did in his paper. Go read it.

Speaker 9: That's for patients who underwent radical prostatectomy.

Speaker 10: An interesting analogy is this volume mission that you talk about. Well, in breast cancer, we unfortunately fall back to a person in site 2 cancer, which you don't call prostate in site 2 cancer anywhere. You've gotten rid of that.

But, what I think is interesting is on MR, people who have DCIS and you get an MR and they don't have a focal lesion, about 60 or 70% of people are that way. The imaging is giving you that 360 view of the gland, and is there an analogy between what you're seeing in breast and what you're seeing in prostate. But if you don't have a focal lesion, that's a high-risk feature. It's something else.

Maybe that's another way that we can try and understand this, and that those aren't cancer, those are high-risk features where you could get, you know, you take the whole gland out, but it could be anywhere. Again, thinking about risk reduction, as a way to reduce that, that's another obstacle I think for us to think in a common way and understand what is that biology? It's often low volume. If you take it out, there's little here, little there, little there. Right?