Brian Helfand: I always noticed that it's late in the day and I'm always talking about the genetics and the room kind of clears out a little bit, so we'll try and keep this as relevant and as interesting as we can here. But, I was charged with the task of talking about genomics. And genomics is very wide... covers a wide range of different tests that we use today to personalize the treatment of men with prostate cancer, whether we're talking about from screening, to diagnosis, to advanced prostate cancer. And certainly as just referred to the media and the different commercially available tests has really got into this space quite well and it's made it quite confusing for the average urologist. Here's just a list of many of the available tests that are offered and these are under the guise of genomic tests, but the vast majority of these are either measuring proteins within the blood and/or RNA measuring protein levels within the tissue.

And so I think most urologists in this room are very familiar with genomic-based tests. These are RNA based biopsy tests that measure protein signatures within tissues to help us decide whether patients are ideal candidates for active surveillance, or whether their outcomes will need other treatments including radiotherapy, et cetera. So again, these are the Decipher®, the Prolaris®, the Oncotype GPS® tests. But what I really want to focus in on, is something that still falls under the genomic name, that is the germline DNA testing. And again, just to distinguish, this is not an RNA or protein-based test, but rather this is the DNA test. This is the DNA that patients are born with, that is passed from generation to generation, and certainly, mutations or variations within specific genes and/or regions within the DNA have been associated with increased risks of prostate cancer and/or different susceptibilities to various reagents and men with advanced prostate cancer.

And I think there are many benefits to genetic testing. So, I think these days when we're talking to patients and/or their family members, it's important to understand why we're getting the test. So, there's benefits to patients in terms of, can we identify those who, for the purpose of screening and/or diagnosis, can we identify those who are most at risk of developing prostate cancer. Again, this is going against the current gold standard, which is assessing their family history of prostate cancer and/or other related cancers. Certainly, we should obtain genetic testing for the purposes of prognosis. This is kind of new onto the scene. If we obtain the understanding of a mutation at the time of prostate cancer diagnosis, would they be appropriate candidates for active surveillance, or should they be more considered for definitive therapy with either surgery or radiation? And certainly, those who have advanced prostate cancer, it's also prognostic, would they be susceptible or better treated with certain specific therapies?

And finally for counseling, what we refer to as cascade counseling, both for the patient as well as their family members, if we find a mutation including a BRCA1 or a BRCA2 type mutation, what besides prostate cancer should they be screened for? And including their family members, are they also at risk? And again, not all genetic tests when we get panels of tests these days, the results that we receive are not used or useful in all different stages of prostate cancer decision-making. There are going to be different panels that we are interested in for prostate cancer screening, example would be HOXB13, certainly when a patient is diagnosed with prostate cancer, we should... there's going to be a different panel of those that are associated with aggressive prostate cancer, and certainly those that are responsive to therapies are going to be different. So again, is understand the purpose of getting that genetic testing, even though they come as a panel. Not all of those genes or the results are going to be useful in every single stage of the prostate cancer decision-making process.

And so, what I want to bring up is a newer type therapy, or a newer use for the germline testing, and that is predicting the prognosis at the time of diagnosis. So, this is based on the fact that it's a reasonable assumption that if a genetic variant was associated with an increased risk of aggressive or advanced prostate cancer, then treatment strategies, including active surveillance or watchful waiting, may not be advised and definitive therapy with either surgery or radiation may be considered at earlier time points. And again, potential caution with vocal therapies should be advised.

And just to give you an insight into some of the data that supports that. There was a recent study, really out of Hopkins in our group, that looked at over a thousand men who were treated with surgery, who had either Gleason four or Gleason five disease, and we compared them to low-risk Gleason six cancer. And certainly, if you had or you were a carrier of either ATM, BRCA2, or MSH2, there was a significantly higher prevalence of having higher-grade prostate cancer, specifically grade group five compared to grade group four disease. And if you look specifically at ATM mutant carriers, they were almost six-fold higher risk of having Gleason grade group five, meaning Gleason eight, nine, ten cancer compared to grade group four.

When we put this into other studies, there's the kind of hallmark study, which is now referenced all the time, and so big deal if they have higher grade disease. What are the implications for these mutation carriers in men with metastatic disease? Certainly large sequencing studies of men with metastatic prostate cancer, we found that 8% to 12% of them either had pathogenic or very likely pathogenic mutations in the DNA repair genes, which include BRCA1, 2, ATM. And so again, so if they have high-grade disease, they're more likely to have metastatic disease. What about lethal prostate cancer? And again, a study in collaboration with Hopkins demonstrated that if you are a mutation carrier of either BRCA1, 2 or ATM, that there was a significantly higher frequency of not only being diagnosed with the more aggressive disease at an earlier age, but the progression to metastasis and mortality was significantly higher. Again supporting that these mutations and this panel of genes were associated with lethal prostate cancer.

So, if you have gene mutations that are associated with lethal cancer, and we have guys who are in our active surveillance programs who carry these mutation carriers, do they fare worse? And if you use grade reclassification as an endpoint in active surveillance, you will see that men who are carriers of either BRCA1, 2, or ATM mutations have a significantly higher risk of going from grade group one, so a Gleason grade six, to grade group four plus three... grade group, three or higher. And if you look specifically at ATM mutation carriers, there's almost a five-fold higher risk of being reclassified from grade group one to grade group three. Again supporting the evidence that when patients are diagnosed with seemingly a low-grade cancer, it may be reasonable to obtain their germline genetic mutation status. And if they are a carrier for one of these, then you would be less likely to continue active surveillance.

And so, if you were going to take this as a take-home point, is that there is strong evidence that would support that if you were a mutation carrier of ATM and BRCA2, that you should really strongly consider against active surveillance. There is some emerging data but it is becoming strengthened, if you're a carrier of BRCA1, CHEK2 or MSH2 mutation carriers, that again a counseling about the risks and benefits of active surveillance should be had and certainly, other gene mutations HOXB13 and a lot of the other genes in the panel probably have no relevance in this setting.

So what about prognosis? And this is the stuff that we are hearing a lot about at this meeting and certainly has made the media, is can we improve the management of men with advanced prostate cancer? And again, in the ideal world, if we can do a germline DNA test that can identify men who are responsive to specific or targeted therapies, it would be a useful test. And so, the interim results of the Phase III PROfound trial, which was I believe talked about here, looked at the results of a PARP inhibitor LYNPARZA®, or olaparib, that looked at mutation carriers.

Ultimately the study was designed to look at DNA repair mutations as a whole, but specifically, a cohort that included BRCA1, 2, and ATM, and then there was a cohort of other DNA repair mutation carriers, and then subjects were randomized in a 2:1 fashion to get either a PARP inhibitor or basically androgen deprivation therapy with either enzalutamide or abiraterone. And the primary endpoint and the interim analysis was progression-free survival. Although there was also a look at the overall survival as well. And certainly, those mutation carriers in particular group A, that had the BRCA1, 2, and ATM, had a significantly greater response to the PARP inhibitor compared to the androgen receptor therapies.

There's also been studies at BRCA2 mutation carriers may be more responsive to platinum-based therapies. And so, certainly, if you look at some of the studies and the... again there's emerging data here which demonstrate that BRCA2 mutation carriers do respond better to platinum-based therapies and have overall improved survival and prostate cancer-specific survival. And then more recently on the scene is the DNA mismatch repair mutation carriers. And again, these are really referring to our Lynch Syndrome patients, those who have MSH1, 2, MSH6 mutations. Again, we get a lot of those patients in our colorectal clinics. Nonetheless, it is also relevant to prostate cancer and advanced prostate cancer. And so, if you look at the overall prevalence of either on the germline mutation having a mutation in one of the Lynch Syndrome mismatch repair genes or what's referred to as microsatellite instability on an analysis of the actual tumor type, you'll see that the total amount is about 3% of all advanced prostate cancer patients. Most of these are within Lynch Syndrome mutations, but the interesting part is that a lot of these are being found to be responsive, which is not surprising from other cancer types to the PD-L1 inhibitors.

Again, we're getting to the point of saying that not everyone should be treating necessarily advanced cancers or dabbling with this, because it is becoming so specific to certain mutation types and this whole personalized medicine movement. And just as a schematic of this, certainly if you are a mutant carrier and BRCA1, BRCA2, ATM and some of the other genes, you may consider earlier treatment or at least enrollment in a clinical trial to a PARP inhibitor or a platinum-based therapy. If you are a DNA mismatch repair gene carrier, a Lynch Syndrome patient, perhaps an immune checkpoint inhibitor. But certainly, this is just the beginning and I do believe that as we explore more, we are going to find other therapies that are designed just for this purpose.

So who should be tested? The NCCN just updated its guidelines and certainly, it has become more inclusive. So, any patients who have either high, very high, regional, or metastatic disease as an automatic should undergo germline genetic testing. Patients with very low, low, or intermediate-risk can undergo testing if they have a family history or intraductal histology. One thing I didn't talk about today was that intraductal histology is a key trigger potentially for germline testing because there is a higher rate of germline mutations in the DNA repair genes in that type of histology. If you look at how the NCCN defines family history, it is relatively on the looser end. It's any first-degree relative or multiple relatives, with less than 60 or a relative who died of prostate cancer, Ashkenazi Jewish history and/or a hereditary family including greater than three cancer members, on the same side of the family.

You can use germline testing for screening. Certainly, if you want to really focus your clinic on men who are most high-risk of prostate cancer, look for those who have family histories of hereditary cancer syndromes, Lynch Syndrome, those who have breast, ovarian, colorectal, pancreatic and other cancers running throughout their family, but also known family members who have these mutations. So do ask your patients, do you have a family member who has breast cancer? Have they undergone BRC1, 2, or other genetic testing?

And again, there are many different models to how to implement this testing in your clinic and there is not a one size fits all manner. And for everyone in this room, it's going to be different for, certainly, you can just refer to the genetic counselor. But the problem is, the genetic counselors are kind of very slim pickings these days because the need is so great and there are not enough genetic counselors throughout the country to answer everyone's needs. So, it is important as a urologist to start initiating these conversations, because, in my opinion, you are the ideal ones to be having these conversations with patients because the genetic counselors can not use the information to really counsel patients about prostate cancer. You have that intimate knowledge. So, we use currently a point of care number two model, where we actually initiate the pre-test counseling and we order the genetic tests. If the genetic tests come back positive, I do counsel based on the implications for prostate cancer, but certainly, refer them to the genetic counselors for future discussions. And certainly, there's other models. And with that, I want to thank everyone in our group, and I think we're going to go to some case examples.

Neal Shore: So, I think for the purposes of time, I would just... let's just finish up with some discussion because we're kind of running a bit late. I don't know, unless she could do the case really quickly.

Brian Helfand: It's your call.

Neal Shore: Oh, I don't know how long ago case is.

Brian Helfand: Well and so...

Raoul Concepcion: Well Brian great talk. I heard Brian give this talk at the Hereditary Consensus Conference a couple of weeks ago in Philadelphia, so this is just one case. We thought we would run through this pretty quickly. So, this is a patient that actually Brian submitted. 55 year-old, second opinion, basically has very low-risk disease. He has one out of 12 cores positive, so we've made these arbitrary decisions for very low-risk, low-risk favorable intermediate based on histopathology and an arbitrary number, of course. So, basically in this patient, what is the role of using hereditary genetic testing? This patient has a family history of prostate cancer, diagnosed at a young age, a family history of breast cancer, but also has a BRCA mutation. So Paul, what's sort of your thoughts based upon Brian's presentation? And for those of you who have not pulled that article that Brian quoted with him and Bal Carter, it's just really a great article. But how does having in a very low-risk patient, how does finding a BRCA mutation influence your decision on treatment?

Brian Helfand: Push a button.

Paul Sieber: I'm going to tell him automatically, he needs to be treated. Man, I think this is a guy that you're going to basically say you don't need a Prolaris® or an Oncotype®. You've got information to say, "You're no longer a low-risk patient or very low-risk". And I don't think activist surveillance is appropriate because he's going to not do as well as you would anticipate. He's the guy who's going to say, "Oh my gosh, why did he do poorly?", and then you've got an idea right now without anything else.

Raoul Concepcion: I mean, so in the these... and we'll cut it off, but I think for all of us in the room, this is going to be sort of the next wave of the next terminologies that we're going to have to start to embrace. There's a whole lexicon out there of what we need to talk... of what we need to understand, MSI, mismatch repair, DNA repair mechanisms, all those types of things.

Neal Shore: So, one quick question because this, I think this is super important. So, you focused a lot on germline, gave a lot of really interesting data, but just a quick look, maybe the three of you respond to the notion about who will you think about getting somatic testing in, versus germline testing, and/or both? Just to, start with you, Paul.

Paul Sieber: So, a typical patient, let's say this patient of mine who presented with bad disease, had a radical prostatectomy, added odd, acted oddly, and he had all the criteria. He did germline testing right off the bat and his germline testing proved negative. So I said, "Huh, germline testing is negative, I'm going to go one step further". And I went back and did somatic testing on his radical prostatectomy specimen, and lo and behold, he's BRCA positive. So, I do germline first for prognosis, for the patient, and for counseling and if it's negative and I'm suspicious, I do somatic testing second.

Raoul Concepcion: No, I think that's exactly right. I think we have to understand germline versus somatic. We have to understand how we're going to use it. Definitely germline in these higher-risk patients for counseling. Definitely somatic testing relative to treatment decisions, lines of therapies, especially in metastatic disease, and I think the real conundrum is going to be in patients with metastatic disease. How are we going to do? Are we going to start incorporating biopsy of the mets in order to get a better look at what they can... what the disease is doing?

Neal Shore: Brian, final word.

Brian Helfand: Agreed. I think germline's the easiest. Certainly, it doesn't change and you're going to capture the vast majority of patients that way. Somatic testing, if it's negative, is very reasonable. You do have to understand that there's tissue available. It's really easy right now. There is no reliable tests on the market that we use that can actually monitor changes. As you expose the tumors to different therapies, the tumor mutation status may also change, so we have to understand that it will become complex, but I certainly think that it's not unreasonable to start doing.