Matthew Cooperberg:  Hi, I'm Matt Cooperberg from the University of California, San Francisco at the Helen Diller Family Comprehensive Cancer Center. It's a pleasure to welcome you to another installment in the UroToday Center of Excellence Series, focused on localized prostate cancer. Today, it is a real pleasure to welcome Dan Lin, who is a professor and vice-chair of urology at the University of Washington and a full member of the Fred Hutch Cancer Research Institute in Seattle. Dan has been a mentor and friend to me for many, many years in urology, and a real pleasure to have him on today. And today we are really going to focus in on active surveillance and the evolution of active surveillance and the role that the Canary PASS study has played in particular. Dan, welcome. Thanks for making the time.

Daniel Lin:  Well, thanks for having me, Matt. As you know, I always love talking about active surveillance and particularly the Canary study and all that. You've been an integral member of course, and as have many across the country, so happy to be here, and thanks for having me.

Matthew Cooperberg:  Great. Okay. Well, to get started, maybe just give us a little bit of the background on how this consortium got started and sort of what inspired it and what the logistics were too. How you actually made this happen. We've talked on a couple of these interviews about the activation energy being not insubstantial for this sort of thing.

Daniel Lin:  Yeah, sure. It was sort of a tipping point event and this happened, I'll tell you over 10 years ago. It was 2007. I can share a few slides, on that if you don't mind. And so here is sort of the origins and just a real brief minute or two. And we started again in 2007. That was 13 years ago. And at the time, this unbelievably inspiring man named Don Listwin, he lost his mother to ovarian cancer, he started an institute or a foundation called the Canary Institute. Founded after the canary in the coal mine for early detection. We need early detection of cancers. And so he started this Canary Foundation years and years ago.  But in 2007, he came to us with a proposal. And then director of the Hutch and Nobel Laureate, Lee Hartwell came to Pete Nelson pictured there and me, and said, "Hey, you guys figure out something for early detection of prostate cancer."

And at the time we said, "We can detect prostate cancer real well." We have PSA. PSA actually detects prostate cancer really well, maybe too well. We need markers to decide what to do once they are diagnosed and let's start doing some active surveillance, which at the time, we look back on it now, and it's an established paradigm, but at the time it was a little bit of an early comer a bit. This was 15 years ago or so. We decided to, let's start a protocol, which we did. We met, we aligned ourselves with the EDRN, which is at the NCI. We have their informatics platform. And then we designed this little study, 500 patients. We knew that was not going to be enough. And then as you remember, we started going and this was 12 years ago. Our first patient was enrolled.

It was primarily a West Coast effort. That was one of the requirements because we wanted to be very nimble, meet easily, talk easily, and fly around if we needed to, when we used to fly of, course, and meet really well. And then with the joining of the EDRN, we kind of went to some of their sites, which are very important, Michigan, the Harvard System with Beth Israel and EVMS. But again, it was mostly a West Coast, UCSF, Stanford. We brought in UBC, our Canadian partners with Marty Gleave, and then eventually we went to other sites and very importantly, central pathology, Jesse McKenney was our pathologist that went from Stanford to Cleveland Clinic. And now we have this study and this is a little of the data slide. We are over 2,000 patients now and I think we are the largest multi-site surveillance study with a biorepository in North America. And that is what we are about. We're about biomarkers, but we are also about studying the disease itself. And we're going to probably get into that in our conversation. That's a little bit about Canary.

Matthew Cooperberg:  As a side note, you don't usually see the map with Canada physically separated from the United States. I think that's probably their preference these days. I think it speaks volumes about the disease that as you say, it's been 10 plus years now, and I think we are really starting to see some of the best successes so far, really just emerging in the last couple of years. Anything that you want to highlight? What do you think the best, sort of unique contributions have been so far from this?

Daniel Lin:  Yeah, sure. Well, I think we can think about it in a few different ways. One is a low hanging fruit, just thinking about we are now a big, active surveillance, multi-institutional cohort. We always think about, obviously at your site, UCSF or Hopkins or Toronto, having big active surveillance studies, single-institution studies, these longstanding studies. Now we have this 10, 15 site study, really that is confirming all the results we see; which is surveillance looks safe, people can be compliant with protocols, and so forth. And I think we are just learning and confirming the natural history of active surveillance.

I think though, discoveries we've made. And recently you've obviously been a major player in that, and you are especially recently with an article in JAMA Oncology. I think we are learning that we know a lot about these patients. We can understand some of their clinical factors. And these are the things that are perhaps under appreciated. Even something as simple as PSA density or volume of the prostate, however you want to look at it, but simple as that, are we really using that appropriately? Because it is a predictor for reclassification on active surveillance. Are we understanding that if a man has a negative biopsy on active surveillance, what that really means? Because it happens 20% of the time. Are we really understanding how to use all the clinical variables together? Or are we just wanting to order a biomarker test or just trying to just see how it goes? I think we are learning that we actually do understand more about the clinical factors. And again, you've been part of this to have a multi-variable or multinomial calculator to understand how men are going to do on active surveillance.

Matthew Cooperberg:  That's certainly been a part of the story, I think over the last 15 plus years. It's just how much we can do with the clinical information if we use it well. But that's been a big part of the challenge though, I think is getting the most information we can out of the clinical information before we then bring the markers and imaging in. With that background, where do you think we are going? And you can maybe comment a little bit on the results you've seen so far with the markers in Canary and give us a sense of where we need to go.

Daniel Lin:  Yeah. Yeah. I think that the markers by and large in active surveillance, let's step back a minute. Realizing that the biomarkers that are commonly used have mostly, at least the tissue-based ones, have mostly been developed in patients that have already had a prostatectomy. They are post-prostatectomy patients. They are higher-risk patients. In fact, let's take Decipher, for example, that was really developed in men with ultra high-risk disease. These men were 60% recurred after therapy, 40% metastases, one in four died of prostate cancer. That was developed on ultra high-risk men, do we think it's going to perform well on active surveillance? Well, we don't know because we haven't really tested it rigorously, but I will say that just thinking about that, many of the biomarkers in the tissue were not really discovered or validated in active surveillance.

And the few series that are out there are a bit conflicting in that perhaps they don't add as much, again, to what we already know about the patients. And so that's the tissue compartment, the blood compartment, and urine. Again, I think the preliminary studies show that they're not adding much once a man is diagnosed with prostate cancer. I'm a little bit hopeful. I'm hopeful. I'm generally a very optimistic person, so I still have hope that the biomarkers can be integrated in. I really do. I just think we need to study them. And I think that we are encouraged to study them and discover more biomarkers.

Matthew Cooperberg:  I'm going to ask you a question that I know you and I have talked about extensively over years now is, how much of the problem is with the markers and how much of the problems is with the endpoints? You mentioned Jesse McKenney, who of course has done a ton of work looking at what Gleason Pattern 4 really means. And of course, it means very different things to different men, depending on the subtype and the extent of disease, et cetera. All of these efforts are based on reclassification to three plus four. Well, if only some of the three plus fours matter and some of the three plus fours don't matter, how are we pragmatically? And I am fully aware that there is no clear answer to this question, but pragmatically, what do we do with that going forward? And how do we design sort of the next set of studies to try to figure out the biology a little bit more clearly?

Daniel Lin:  Sure. Sure. I'll say this, you order some of the biomarkers on your patients and you are going to get a report. And a few of the lines in that report are for the probability of prostate cancer-specific mortality and for the probability of mets(metastases). Which is always low single digits or it is incredibly, in my opinion, useless information for a low-risk patient. All right. And so those aren't appropriate endpoints, we know that. Which brings me to the thing about reclassification. Yeah, it's this from a three, three disease to a little three-four, and you are right, some three-fours make a difference and some don't. It's asking a biomarker a lot to find that, I think. Now I'm not sure it's asking a biomarker too much to find someone that stays three three every time. Three three, three three, three three, or negatives and so that is non-reclassification.

I think that's a great endpoint that basically, the way I distill that is, maybe we need to be looking at biomarkers for the safety of active surveillance so we can tell a patient, "You are safe to do this. Very safe. You're not going to have any bad event in the next five to 10 years. Don't even do biopsies." I think we can do inactive surveillance, inactive surveillance. I think so, with the end of biomarkers, now that would be a better endpoint than let's say, mets or death from prostate cancer. For sure. There are some intermediate endpoints that we can talk about, maybe recurrence or bad pathology after being on active surveillance or something like that, bad pathology in the prostatectomy specimen. But at this point in time, I think very little has been done on clinically meaningful endpoints in active surveillance simply because the studies haven't been done on true active surveillance patients.

Matthew Cooperberg:  Well, this gets to a point that you and I made clear in the paper you referenced, which is exactly that, that the non-reclassification has a very good negative predictive value for not dying of prostate cancer. If you reclassify, maybe eventually you might die, maybe not.  But if you say three three, as you say, three three is a non-metastasizing entity.

Daniel Lin:  It is. I agree. I tell all my residents, they all know this and trainees, I say, "NPV is king." It is the highest bar, I think. It means that if a test is negative, whether it's a biomarker or a clinical model or whatever comes out as a negative, how truly negative is it? If we can tell someone that you have this test or this model says that you are 90 to 95%, hopefully, more than that, it's negative for having a reclassification event. That is industry standard, very high bar, a lot of biomarkers use that, whether it's SelectMDx or ConfirmMDx, a lot of these ones that are out there in the market, NPV is very important.

Matthew Cooperberg:  How does that form studies in Canary going forward? How do we operationalize that, I guess, I'm asking? In terms of thinking about the next set of biomarker studies?

Daniel Lin:  Yeah. I do think that we can use a base model maybe, and the base model might be a model well, the one that you were the first author in JAMA Oncology in publishing the model of, if you put in PSA, policing PSA kinetics, negative biopsy, prostate volume and everything in a model and it forms a base model to say, "Hey, this is the bar to jump over for biomarker studies." I think that is a very good place to start. Again, I'm very hopeful and optimistic that we can incorporate other markers probably on a discovery level to perhaps add to that model.

Matthew Cooperberg:  What about MRI? Is that solving all of our problems in active surveillance? Not that that's a leading question.

Daniel Lin:  No, I know. Again, you and I have discussed this and been in conferences and advisory board capacity for MRI and other biomarkers. I think that MRI has a role. And if you think about it, I was thinking of this the other day and some of the pros of MRI are the cons against biomarkers, I think, and vice versa. If you think about MRI first to be fair, it is looking at the gland of interest. It is looking at the target. It is looking at it. It's not thinking about a circulating biomarker out here in the urine or the blood or the tissue biopsy that is happening to hit it. It's the thing. That is what is really good about it.

The problem with it is the reproducibility of the imaging. Whereas the biomarker over here, it is very predictable. You look at the coefficient of variation on a biomarker, you order a PCA3 or you order a 4Kscore, that's what you are getting. The coefficient of variation is 5% or less. And it has to go through the rigors of FDA and, so forth for it to be an LDT. And so that is a very reproducible test.  Whereas an MRI is not, as you know.  You show that to my person here in Seattle, you show it to your person there at UCSF and it might be different, although we just have someone from there.

Matthew Cooperberg:  Our guy, yeah, you just got our guy.

Daniel Lin:  Yeah, Westphalen, here, but you are right, there is, and he published a paper that showed amazing differences. I think that the reproducibility on the MRI side is poor, unfortunately. And so then it affects both positive predictive value and negative predictive value. I do, being as I have always said, a hopeful person, think that we might solve that a little bit with some computer rated diagnostics, some AI, or something that can help the radiologists and the pathologists on the other side, discern more consistently lesions. I think we are getting there, or they are getting there.

Matthew Cooperberg:  Yeah, no, his paper, Antonio Westphalen, his paper, he showed 25 to 75% PPV for PI-RADS four or five for finding high-grade disease. And that was in 25 big academic centers. That is troubling.

Daniel Lin:  It is troubling.

Matthew Cooperberg:  And it makes me wonder how the UK is doing what they are doing with this MRI as a second test, no MRI finding, no biopsy.

Daniel Lin:  Yeah. Okay. I'll tell you a couple of things and the Europeans will listen to this I'm sure. And I think that, there is data on the active surveillance population and MRI to warrant that? I'm not really so sure. I will say though, that if you look at the Cochrane review, it was in European Urology and you know this. That Drost, D-R-O-S-T, and others published multiple meta-analysis and so forth, you look at that, the additive value of MRI in the initial biopsy looked like it was 5% and it wasn't statistically significant, but the additive value for repeat biopsy population, and again, this is nondiagnostic setting, before the diagnosis, was 44%. That was very advantageous. You might translate that to say, "Someone has already been diagnosed with prostate cancer in active surveillance, they've already had their biopsies, the additive value in MRI might be more like a repeat biopsy maybe," and so I can kind of see that translating, but it hasn't been well studied in my opinion to say, "Don't do a biopsy in active surveillance."

Matthew Cooperberg:  We just had a study, Carissa Chu, at our place, just did a look at our series. And it was interesting, the MRI at the confirmatory biopsies, because we were looking at the NPVs and the first confirmatory biopsy was not that great. But once you get into surveillance with two biopsies under your belt, it starts to look better as a biopsy replacement.

Daniel Lin:  I can see that.

Matthew Cooperberg:  I wonder if that's where we're heading?

Daniel Lin:  I could probably see that or else one could understand maybe trying to do a lower cost biomarker to reflexively to say, do an MRI or maybe vice versa. Everyone has their own angle on that, but I definitely could see that.

Matthew Cooperberg:  What are the other key questions in active surveillance in research and clinical practice? Where do you see the field going, Canary, or otherwise in the next five years or so?

Daniel Lin:  Yeah, sure. Well, I think that we have a long way to go on understanding decision making, quality of life, anxiety that surrounds men on active surveillance and how that plays into their decision making. I think we have John Gore here, at our site, is one of the gurus in patient-reported outcomes and is trying to understand the role of well, patient education, physician education, certainly, but just anxiety and the quality of life that is impacted with a diagnosis of prostate cancer. Obviously, you and I have talked before about trying to rebrand lower grade prostate cancer in a way that is a little bit more palatable to the spirit of men and their families so they don't have to walk around every day with a ticking time bomb cancer in them. It can be something else. I think we have some push to go there.

And then the other thing is whether we really think that some of the models that we are doing all this on, are biomarkers change decisions but change decisions in the right way. And so we have to understand this may be more on a population-based level or with bigger randomized trials in some way to understand the impact of the knowledge that we have gained for the last 10, 15 years on active surveillance. Again, I'm still very hopeful that we can find or convince some companies that are in the biomarker world to do some really good studies in active surveillance biomarkers. But in lieu of that, we have all these other things and a little lower hanging fruit, but a lot of other fish to fry in active surveillance.

Matthew Cooperberg:  Do you think it's mostly anxiety, the barrier to get us to where we need to be nationally? We've gone from 10% to 40%, 50% in Capture, AQUA and other data sets, active surveillance across the country, which is probably still, it's a lot of progress, but we should probably be somewhere around 80 like they are in Sweden for low-risk disease. What do you think it will take to get us there? Is it anxiety management? Do we need financial models? What are the barriers?

Daniel Lin:  Yeah, I think that, well, you mentioned two of them, the big ones I think are anxiety, but it's not, and I don't want to paint it all in terms of patient and family anxiety because I think it's physician as well. It's our worry about missing the window of curability. I think that some of the legal background worries on a physician's practice level are real. Obviously, I'm in an academic center, it's a little different, but I do think that those things very much matter. And then you bring up the financial aspects. I think that's there. No one's really looked at it to any extent. I do think that cost-effectiveness and clinical utility go hand in hand. That hasn't really been studied really well. There have been a handful of papers. There have even been some papers showing that active surveillance overall, is more expensive.

You know, biopsy, biopsy, biopsy, biopsy, prostatectomy. And so I worry a little bit about that as well.  But I also know that over treatment with loss of work and incontinence, erectile dysfunction, some of the other things, cystitis or proctitis with radiation, those are real things. And so it is definitely a balance. We have a long way to go. We know that we are not doing the wrong thing though by watching men with low-risk cancer. We just have to learn how to pick which one is better.

Matthew Cooperberg:  Last question. Do you think we have the right infrastructure to ask these questions going forward? Canary is obviously a huge step in the right direction. Do we have enough? Is there enough infrastructure within the existing multicenter groups, like SWOG and Alliance to get at active surveillance? Or is this just sort of below the radar because we're not usually talking about pharmaceuticals? Now, do we need a different consortium to do the big trials, to do the hard things? I remember a conversation with you and Ian Thompson years ago about doing an eight versus two-year biopsy. We spent six hours in a conference room. This was for SWOG, I think. What would it take to get big surveillance trials onto a cooperative group right on?

Daniel Lin:  Yeah, so a couple of things. In all disclosure, I'm the co-chair of the SWOG prostate subcommittee and co-chair of the NCI task force for prostate cancer so I see all the NCT and trials and there is a little bit of a mixed answer there. One is that certainly most of the big trials are driven by therapeutics so they are driven by money. And I think that they are also driven by the set of patients that are actually dying of prostate cancer, so not low risk. That's number one.

Number two, I think that in large part, the NCTN, the National Clinical Trials Network, SWOG, Alliance, ECOG, NRG, they are more and more being reserved for trials that would not be done by pharma or are difficult to be done by pharma because pharma will get it done quicker and they are a little bit more nimble and that's what you get. And so I do think that active surveillance can be within the NCTN. I really do. Kelly Parsons had the MEAL trial, so that was. There is a place for it. It just demands persistence. I will say that within the NCTN there is a whole group of just radiation oncologists. NRG is radiation oncology and so there is no cooperative group. I think you and I were discussing before that our corner is more surgically oriented, like urologists and there was ACOSOG. American College of Surgeons Oncology Group, they had a group that is now dissolved.

It's a great discussion. I think that you and I and others that are leaders, we should think about something like this, again, with urology surgeons, urologic surgeons. Now recall, remember, NRG has a bunch of groups and there is GU, is just one subcommittee. They do a lot of great trials. And if there was a surgical committee that GU was one part of, I would love that. Right now there isn't. But again, just taking into account Kelly Parsons' MEAL trial, and I think that active surveillance has a place, it just demands getting on the circuit. There was a focal therapy trial that was discussed, it's right now on the back burner, but that was kind of focal therapy versus active surveillance. And so that was out there. And I think we have to keep pushing. We definitely need to encourage everyone listening to go to your cooperative groups and push for trials in early disease.

Matthew Cooperberg:  Excellent. Any last thoughts on surveillance and where we are going?

Daniel Lin:  No, I appreciate you highlighting us. And again, I say, I think I'm very optimistic that we have more to go, not just on the guidelines. It's on the guidelines now is preferred, but we have more to go. We are going to get biomarkers on there hopefully and models.

Matthew Cooperberg:  Awesome. Thanks so much for your time. Always a pleasure, Dan.

Daniel Lin:  Yeah. Thank you. Take care.

Matthew Cooperberg:  Take care.