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Speaker 1: Let me ask you, in the UK, if diagnosing grade performance as a medical error, is there discussion along these lines, or how would this concept of not calling incidental be received, or does this conversation happen?

Speaker 2: I think it wouldn't make a big difference to our rates of surveillance, but it would because we do spend a lot of time talking to men, and we go through all of that. So I don't think it will make a big difference to the rates of surveillance, but it will certainly, from my perspective, I'd just like to get them back into the community and not have them. So this argument about, well, we should continue to intensively monitor them, we shouldn't. We should just get them out, set some thresholds for their PSA to be referred back because that's what we do with the negative MRI patients. They're no different than negative MRI patients in my mind.

Speaker 3: And Matt, in the breast cancer screening in the UK, same thing, they have a very organized screening program. The cancer biopsy rates are 50% compared to ours, which are about 20%. And if you over-biopsy, same thing. They're at your doorstep, what are you doing? Take the performance test, you're out if you biopsy too much. Their DCIS rates are half, they screen every three years starting at 50 to 65. Very different.

Speaker 4: Here's that. All the things that we've said; see, it appears that the screening pattern has been fixed and it's making the things that we shouldn't worry about become less of an issue.

Speaker 3: That's correct.

Speaker 4: We are going backward. We've actually lost the battle on screening and now we are trying to change the Gleason so we kind of, in the US, I mean we got to create a—

Speaker 1: Double problem, right? I think there's little question that part of what drove [inaudible 00:01:40] up finally in the US is the task force. Same to Tim's point earlier, it's all about harms and benefits, and the harms of overtreatment were right out by the task force as far as excessive benefits. And I think that message, whether or not it's properly admitted, I think that message has been part of what's driven American urology and British [inaudible 00:02:00].

Speaker 3: Oh, maybe it's time for risk-based screening, risk assessment [inaudible 00:02:04].

Speaker 5: Someone said that the recommendation would not change because the oncology benefit, it's the same, I mean slow. So there seems to be not an emphasis on a therapeutic index or benefit-to-risk ratio, it's more of the oncology benefit. So if you preclude overtreatment, then you do remove harms. But it seems that the pathway doesn't care about that.

Speaker 2: I think the task force and the national screening committee in the UK, they overly play the impact of CAP and PLCO. So they put all of that in the wash with the European study. The national screening committee in the UK has done as well. They will say CAP is still relevant, it's a screening study. We'll scream out loud that it's just a one-off PSA. And they'll say, well, it's still a screening [inaudible 00:02:56]

Speaker 3: Very, very low adherence to—

Speaker 2: They don't care.

Speaker 3: Terribly.

Speaker 2: It's a screening study and therefore it muddies the water enough that it dilutes the benefit of her spec and therefore the benefit is in the net.

Speaker 6: But I think there's an interesting point here that relates to also talking about international application, and that is whatever efforts are done, for example, in the UK to drop down that diagnosis of grade group one, the extent to which that is successful then impacts the size of the population that would be relabeled.

It may also affect the men who, if you have a very fine filter and only a few men get through to be diagnosed, there is a question as to whether they are representative of what used to be before the fine filter was applied. So I think there's kind of a continuum here. At a certain point, if we were able to not diagnose grade group one, this whole discussion would be moot. And so the extent that the filter that we have, whether it's imaging or I don't think we can ignore the fact that there is still a lot of work going on on the reflex biomarker front, there are still efforts to try to make a finer filter here in the US and I think we should keep an eye on that because I don't think it's an absolute yes or no. It's really that by the time they come to the relabeling question, there's a lot that has happened before that and we should bear that in mind. And also could help to put the international, the different settings on a continuum that we actually can understand. Yeah. Sorry, Laura had a question.

Speaker 7: Quick comments. Targeted biopsy, I think at least 35 or 40 percent of the ones I do come back grade group one of the patients who are diagnosed with cancer. So your experience is very different from mine and I'm just curious if others share that. I think in the literature it's also very common to find grade group one on a targeted biopsy. My second point, another thing you said that I didn't agree with—Grade group one is not the same as having a negative biopsy in terms of the likelihood of occult higher grade cancer. My interpretation of grade group one, basically it's a marker for a higher increased risk of high-grade cancer. The higher the volume of grade group one, the greater the risk. A lot of people have looked at that. So you made the comment that it was as if it's a negative biopsy. It isn't really.

Speaker 2: So I think the issue is the proportion of PI-RADS 3s that radiologists report. That's where you see these shifts and there is variability in the UK on that front as well. And the more PI-RADS 3s you call on MRI, you will biopsy those more and you will find more grade group one, but usually small volume. I agree. The high volume Gleason sixes do seem to be a different entity, but you can, is it because they have a tiny bit of grade group, at least some pattern four within them? Or is it because they are biologically distinct? That is going to be a critical question. So I don't disagree with any of us. But yeah, I mean the majority, we know when we don't biopsy a man that he stands a one in three chance of having a tiny little bit of prostate cancer, maybe even a one in five if you look at the autopsy study. So in my mind they aren't that different.

Speaker 8: Yeah, I was going to say we've talked a lot about high-volume six. It's actually really rare, right? I mean it's the minority upon minority of really high-volume six. It's interesting to me that we can kind of basically get around, we don't want to find low volume Gleason six cancer, but we can't seem to get around disagreeing it's not cancer. So fundamentally—

Speaker 9: The impact then of changing what we call a nomenclature change would allow us, whatever it was verbalized as to us as a clinician, we would then be able to put that in the context of yes, there's a visible lesion there, I see they maybe have a high PSA density. This is now someone who's going to be the new active surveillance versus the one who, look, you don't have cancer, it's not visible. We can deintensify your surveillance now and just follow up potentially PSA. And they don't have this overarching emotional burden of being a cancer patient now. I think that's the win in my mind in that situation. So it needs to be however this thing is worded, it allows us then to then incorporate genomics, MRI, what have you to decide on how that patient's going to be managed. Is my say.

Speaker 10: Can I ask a question ahead?

Speaker 6: How would you manage with PSA if a person now already has basically got a positive for an abnormal level, would it be in terms of change over time? We're struggling with this in defining strategies for our modeling. We want to have a strategy where a man comes back and it's just PSA, but clinically what do you think is a reasonable approach? And it may be tailored to each person, but they are already above four or whatever people are using for an age-specific cutoff or something.

Speaker 9: I really look at, with MRI now, almost all my patients get it. We look at density and whether that's changing. A man with a 150-gram prostate and a PSA of six and a negative biopsy, I mean, you're fine.

Speaker 1: The canary model I've seen allows for really individualized tailoring and works well. We can probably enhance that with markers. The only difference in my mind is, do you call a guy a cancer patient in the meantime? You would follow the same way with the same tailoring based on the same parameters. The only question is does he deserve to [inaudible 00:09:15] that way?

Speaker 2: The only thing, Ruth, with the PSA density is you do need to do the MRI because a low PSA density with a PI-RADS 4 or PI-RADS 5 lesion needs to be biopsied and probably not discharged because if you've not found cancer and not found inflammation, you probably missed the cancer. So the MRI is really critical. I know Andrew wants to ask me a question.

Speaker 1: All right, last one and then we're going to do the last bit of this section. Go ahead.

Speaker 11: Oh yeah. So it's sort of funny because Hash and I are seen at opposite ends of the spectrum for a long time. It's like Hash is the major advocate of MRI and somehow Andrew's anti-MRI. And that's interesting. Actually, I thought we were on totally the same page because I always said the problem isn't MRI, it's MRI plus current approaches to grading plus current approaches to treatment, and Hash you said, "I agree," but then you just said something that really rocked my world, which is we're trying to get rid of active surveillance in the UK, which sounds like if you find low volume pattern four in a three plus four patient, then you're going to treat them which—

Speaker 2: No. So it was a comment made in 2015, 2016 to Chris Parker, and at that time nobody was really thinking about surveying low volume pattern four. We now do survey a lot of low volume pattern four because Caroline's data shows really nicely that they behave very differently, especially if they don't have an MRI lesion. So it is just an evolving thought process.

Speaker 11: I think this renaming is going to be very good for MRI, right? Because let's find absolutely everything that's there and then we've got a great quantification of what's there and then most of it isn't cancer and then what's left? We can say, well, that's not very much cancer. So we can follow that.

Speaker 2: Yeah, I agree.

Speaker 1: All right, we're going to do our last one.

Speaker 9: Yeah. I just want to state the facts here because we've been talking about this all day about the basement membrane. So let's just clarify that for prostate, this is a fact. When we assess invasiveness, we look at the basal cells. Now that's intriguing. Basal cells are a surrogate of the basement membrane. If you ask me, is the basement membrane equal to 100 percent basal cells? I don't have the answer for that. If you ask me if glands without basal cells have invaded the basement membrane, I don't think anyone can answer that question. So basically our invasiveness is based on basal cells, not the basement membrane.

Speaker 2: What I'm saying is that change that you see, how have you validated that it's relevant?

Speaker 10: Right?

Speaker 9: Yeah, I understand. I understand. But my point here is that—

Speaker 10: This is a really important point—

Speaker 2: The fundamental basis of why 80% of pathologists don't agree to change. What is your validation of that histopathological finding?

Speaker 9: Yeah, the point I'm raising here is that if someone says there's an invasive cancer there at GG1 without basal cells, if you ask me, would that gland have penetrated the basement membrane? No one knows.