Alicia Morgans: Hi. I'm delighted to have here with me today Dr. Adam Kibel, who is a Professor of Surgery at Harvard Medical School, and who is also the Chief of Urology here at Dana-Farber/Brigham and Women's. So wonderful to have you here.

Adam Kibel: Oh, it's a pleasure. Thank you for having me.

Alicia Morgans: Well thank you. I wanted to talk with you about a lot of the changes that are happening in urologic oncology, particularly as they relate to prostate cancer. A lot of what we're thinking about is identifying high-risk patients, and some of the identification of high-risk patients can even go as far as being related to genetics. And I'd love to hear your thoughts on that, and then we'll think through all high-risk localized prostate cancer and how we think about that disease state.

Adam Kibel: Yeah so, I've always wondered whether or not we can identify these patients that are at risk for developing Gleason 7, 8, 9, 10 cancer; the intermediate and high-risk disease, earlier in the disease process. Maybe even prior to when they would actually develop the disease. And maybe at the same time eliminate the need to screen patients that are only at risk for developing Gleason 6 cancer. And I think that genetics are one of the tools that we have at our disposal in order to do this. There have been a lot of studies looking at genetic variants snips. Single nucleotide polymorphisms, these small changes in the DNA, tiny misspellings, and whether these ones increased your risk of developing a disease. We have well over 100 of these that are associated with an increased risk of prostate cancer.

Until recently we really didn't have anything that predicted somebody has an increased risk of developing aggressive prostate cancer, which is really what we care about. And why is this important? Because then maybe we could only screen the patients that are at risk for developing aggressive cancer. Maybe those are the patients we'll put on prophylaxis. I'm not advocating this, but there are people who've talked about prophylactic prostatectomy in patients that have high-risk disease. That seems sort of far-fetched, but we do that for breast cancer.

So now that we can sequence very deeply, and we cannot look at the single misspellings, but we can essentially look at the entire book. We're starting to find that there are some genetic variations, particularly in DNA repair enzymes, that are associated with more aggressive disease. The one that sort of leaps to mind is the one that's when I say most actionable, we can talk about this. I'm not exactly sure what the action is, but is BRCA2, which has clearly been associated with more aggressive prostate cancer. Until recently I'm not really sure it's been actionable, but Bal Carter just published an interesting study looking at patients that were on active surveillance and found that some of the patients who progressed were ones that had BRCA2 mutations. And so that's our first hint that maybe we can start taking all of this research, all this data, and maybe start applying it to our patient population.

Alicia Morgans: So how do you treat a patient? Say there's a patient with a BRCA2 mutation who has Gleason 3+3, and who is on active surveillance. And your eyes are getting wide because there's not necessarily data here, but how do you put that patient on active surveillance and potentially follow that patient, knowing with this data, and with just Gestalt that that patient probably has a higher risk of progressing on? And assume that we only know the patient is BRCA2 positive because of family history or something. Because we would not necessarily screen for a patient with low-risk prostate cancer that's localized for genetics.

Adam Kibel: Right.

Alicia Morgans: But go ahead, how would you keep that patient on surveillance or would you keep that patient on surveillance? What do you think?

Adam Kibel: So, two years ago I wouldn't have even thought about it. I would have put them on active surveillance. I would have said, "Well I guess, you got to monitor the women in your family, your children, your girls. To think about whether they're at an increased risk for breast cancer down the road," but it would never have popped into my mind that it was associated with prostate cancer. There were some hints that BRCA2 was important prior to two years ago, but the hard data wasn't there.

But you know over the past two to three years, there's really been a lot of hard data. I think I'd have a lot of trouble putting that patient on active surveillance. I would probably tell them, "I'm very nervous about this. This is associated with a very high-risk disease. If you really want to be on active surveillance, and you insist on it, we'd want to monitor you more closely. Get many more MRIs. Repeat the biopsy much more frequently."

I'm not a big fan of the yearly biopsy. I think it's too much on the patient. There are too many risks of infection, and I don't really see a huge benefit there. But this is the kind of patient that I really would want to do repeat biopsies on. I am not endorsing this now in any way, shape, or form. But I wouldn't be surprised in five to ten years if you have the right BRCA2 mutation, that you don't even need to have the diagnosis of prostate cancer. It's entirely possible and plausible that those patients might undergo prophylactic prostatectomy. I want to be clear. I'm not saying we should do that now.

Alicia Morgans: Of course.

Adam Kibel: But the way this is evolving, our whole view of this is changing year by year in a very rapid way.

Alicia Morgans: I agree and just as you mentioned, a couple of years ago we would have that patient on active surveillance without any problems. But knowing now what we know, that's much harder to do. I know there are a lot of questions, and we talk about these patients in tumor board about whether these patients should be on active surveillance or not, and with low volume low-risk disease, there's always this wish to have those patients on surveillance.

I hope that over time, either groups that are studying active surveillance intensively can tell us what happens, is it safe or not? We definitely have to answer that question, but your reticence is the same reticence I have. I look forward to seeing how that really plays out for patients because we don't want to over-treat patients. But these are patients with high-risk disease, and we don't want to undertreat them either.

Adam Kibel: The Bal Carter paper that we looked at at Hopkins looked at their large active surveillance cohort and found that the patient didn't progress to death, but they did not stay as Gleason 6 cancers. Those were the ones that progressed to Gleason 7 and above that had BRCA2 mutations. They weren't the only ones that progressed, but they were certainly patients that were at higher risk. Sort of tells me that that's not a good patient population. I think interestingly, most of the patients that I see that have BRCA2 mutations now are patients where there's a family history of cancer. It's not like we're screening the general population for these kinds of things yet.

The patient usually presents with an understanding of cancer that's a little bit more nuanced than the person who presents with, "There's no cancer in my family, and I was just biopsied and I have Gleason 6 cancer." They're usually somebody who has family members that had a BRCA2 mutation. That's why they were screened. They had a risk of breast, ovarian, other cancers usually in the women in their family, but they understand the concept that they're at an increased risk for having a bad outcome. Unfortunately, many of these patients, actually when you delve into it, have a history of family members dying of cancer because it is associated with more aggressive disease in a multiple different types of cancer.

Family members, if you have a family member who died of a cancer irrespective of what was the underlying cause, whether it's a genetic cause or you don't know. Active surveillance is really hard on those patients. Even if you have someone who has Gleason 6 cancer, and say their dad died of prostate cancer, I find it's impossible to keep that patient on active surveillance no matter how hard I try.

Alicia Morgans: Well, and that's true of women with breast cancer with family histories too.

Adam Kibel: Right.

Alicia Morgans: BRCA2 often leads to women having prophylactic mastectomies in that situation, because it's not just understanding the risk of the cancer. It's understanding all of the aftermath and all of the suffering and what it can entail. I totally agree with you, and I think that it's important for us to tailor our treatments and our follow-up strategies to these patients. Keeping in mind both their cancer-specific risk as well as their psychological risk when we're putting these things together.

One thing that you mentioned was the integration of MRI into the follow-up strategies for patients on active surveillance. I'd love to hear how you think through that because MRI is becoming increasingly used both in a screening sort of methodology as well as for follow-up for patients on active surveillance to avoid things to like an unnecessary biopsy, or perhaps target our biopsies to where the place that it matters most.

Adam Kibel: Yeah, so I think MRI is still an evolution. It's a huge leap forward, but it's still an evolution. It's incredibly dependent on the machine that's being used. You need to have a 3 tesla magnet. I wouldn't be surprised in the future if we keep on upping the amount of tesla that we use. The right signal acquisition has to be done, and then the people reading the MRI are incredibly important. It is really a skill that I think is underappreciated by people who don't try and read these, but as a urologist who sits there and reads CT scans all the time, bone scans, and say, "Oh I clearly see that. I can clearly see that."

MRIs are much more tricky, and I think as our radiologists get better and better at reading them, particularly out beyond the academic centers where the innovation started, to begin with, it's going to become really central to our management of these patients. Both in the screening domain and in the treatment and management domain. At the same time, I think there's a little bit of over-reliance sometimes on the MRI. The MRI is negative, the patient's PSA is climbing rapidly, and people say, "Oh they can't have cancer." That's not true. I mean we see patients all the time who have negative MRIs and clearly have aggressive prostate cancer.

The landmark studies have sensitivities and negative predictive values that are not perfect. That means by and large the patients that have aggressive cancer are missed by the MRI, and if you have a negative MRI, that doesn't mean that you don't have prostate cancer. For instance, the landmark study from the University College London, it was a multi-institutional study. So I don't want to give them all the credit.

Alicia Morgans: Of course.

Adam Kibel: But they were the first authors in it. They showed that the negative predictive value of an MRI was 76%. That's in a 1.5 tesla magnet. Clearly, maybe it'd be better if it was a 3 tesla magnet. But that means that a significant percentage of the patients who have a negative MRI have Gleason 7 cancer because that was their endpoint. Not cancer, it was Gleason 7 cancer.

In my view, the MRI is useful in terms of making sure you didn't miss something in a patient who you really want to avoid a biopsy. Let's say a patients has a PSA of five, and they are 80 years old. You would say, "Look, let's get an MRI. Make sure there's nothing terrible going on." I think it's really useful then. I think it's really useful in patients that have had biopsies and you're trying to avoid doing another biopsy. I think it's very useful in somebody who needs a biopsy and you want to find a target. I wouldn't be surprised if in five years people who have a negative MRI can avoid a biopsy, but I really just don't think we're there yet.

Alicia Morgans: I agree. I think that there are definitely movements in that direction. That there is interest, and certainly from a patient perspective, we can all understand that we want to try to limit biopsies. Because even as you mentioned before, biopsies have their own risks of infection, discomfort, time that it takes to do the biopsy. At least an initial diagnosis, to me, the tissue is always going to be the issue, but we'll see where the field goes. It's really important to keep that in mind.

Adam Kibel: Right, I agree. Unlike in kidney cancer, who will remove part of the kidney or the entire kidney on the base of imaging, nobody's removing a prostate on the basis of an MRI. And that just shows to me that we all know that it's imperfect and that there still is room for improvement.

Alicia Morgans: Absolutely. To get back to that patient that you mentioned. What about a patient who has had a rising PSA, maybe negative standard biopsy, MRI that's negative. What do you do with that patient?

Adam Kibel: Well it depends on how much the PSA is going up. If the PSA stays relatively flat, and by that I mean it's going up by .1, .2 every year. I'd reassure that patient. I'd say, "It's probably due to BPH." One of the beauties of the MRI, is we start to get the size of the prostate so we can actually calculate a PSA density relatively easily, and that's very reassuring. I mean, patients come in with a prostate of 100cc's, and they have a little bit of Gleason 6 cancer. They have a negative biopsy, and their PSA is between 4 and 10. I feel so comfortable now telling them, "This is just because your prostate is really large."

Which was not true in the past because you had to get an ultrasound, and once you were getting an ultrasound there was this push to get a biopsy because you've already done all the work. I think that's a really useful way of reassuring yourself and the patient there's nothing going on. If the PSA is skyrocketing, well obviously if it's going up incredibly rapidly, it's a 4 and then a month later it's a 10. Then you start thinking is this-

Alicia Morgans: Metastatic disease?

Adam Kibel: Well no, no, I think infection.

Alicia Morgans: Oh infection, yeah.

Adam Kibel: I think infection. I think other causes, and the first thing I'll do is I won't treat them with antibiotics because that's been shown over again not to be useful. But if they have symptomatology I'll treat them with antibiotics. If they don't have symptomatology I'll say, "Let's check it again in a month and see what happens, or two months." You'll often find that it's come back down. Because if they have metastatic disease, I don't think there's going to be a huge...

Alicia Morgans: Discrepancy on imaging.

Adam Kibel: ... Discrepancy on the imaging and things like that.

Alicia Morgans: That would be unusual.

Adam Kibel: If someone’s PSA is going up, say two... It's gone up by two nanograms in a year and that's reproducible. I would do a second biopsy. Even if the MRI was negative, and I'd try and get some transition zone cores. Just to try and get some of the tissue from the anterior aspect of the prostate. It's amazing how frequently you find more aggressive cancer in those patients.

Alicia Morgans: It's important to recognize that the negative predictive value of these imaging strategies is certainly not perfect.

Adam Kibel: No.

Alicia Morgans: And that if we clinically see something that looks like prostate cancer, it's going to be prostate cancer based on the PSA doubling time, despite negative biopsies and negative imaging. Continue to think like the good clinician that you are and go after it again maybe.

Adam Kibel: Right. One of the things I tell patients all the time is, "We treat patients not numbers. Not images, we're treating patients." That's what I try to emphasize to the residents over and over again. Your job is to take all the information, synergize it into what you think is going on. Because unfortunately we don't know what's going on in that patient, and then act accordingly. Nobody likes a biopsy. Nobody wants a biopsy, but let's face it, a biopsy that saves one in ten patients from developing metastatic prostate cancer? That would be a fabulous outcome.

Alicia Morgans: Absolutely. Well, thank you so much for sharing your expertise and this really clinically relevant guidance. I really appreciate your time today.

Adam Kibel: Oh no, it's a pleasure. Anytime.

Alicia Morgans: Thanks.