Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University. I am so excited to have here with me today friends who are here to talk about genetic testing, genomic testing in GU cancers.

First, let me introduce Dr. Colin Pritchard, who is an Associate Professor of Laboratory Medicine and Pathology at the University of Washington. We also have Dr. Heather Cheng, who is an Associate Professor of Medicine, also at the University of Washington. And finally, we have Dr. Petros Grivas, who is an Associate Professor of Medicine at the University of Washington. We just have a whole crowd from Seattle here to talk about molecular diagnostics and testing in GU cancers. Thank you all for being here.

Colin Pritchard: Thanks for having us.

Heather Cheng: It's a pleasure.

Alicia Morgans: Thank you. So, just to start us off, let's talk a little bit to Dr. Pritchard about the role of the molecular pathologist and molecular diagnostics in GU cancers. This is relatively a new and evolving field for us. It's more developed and advanced in prostate cancer, but it seems to be on the verge for the other GU cancers. So what are your thoughts as a molecular pathologist?

Colin Pritchard: Yeah, it's an exciting time to be a molecular pathologist, particularly in GU, and as you said, particularly in prostate cancer now that genetic testing and prostate cancer is really a standard of care for men with metastatic disease, there's such an increasing role in that molecular testing. And then of course, just to kind of explain what a molecular pathologist does, not necessarily traditionally looking at slides under the microscope as much, but looking at genetic data, both on the tumor side, but also on the germline or inherited side and helping oncologists and other cancer providers, urologists, to interpret those findings to best help their patients. So, maybe I should say a little bit more about what I do because my field is growing, but a lot of people don't have a molecular pathologist yet.

So, we both run labs that do the testing. We can interpret those tests. We can interpret tests even from outside commercial labs sometimes. We run molecular tumor boards often where we have multi-disciplinary teams that talk about results and really help interpret the intricacies of the data. It's become so complex with the interaction between germline and tumor findings. And now the complexity of different specimens, like doing liquid biopsies, cell-free DNA testing, it's really fraught with peril, particularly because there can be interferences from non-prostate cancer sources or non-other urothelial cancer, whatever your measuring sources. So, the molecular pathologist can help navigate all those results, both generate the results and navigate the results to really provide the best care for our cancer patients.

Petros Grivas: Thank you, Colin, for this insightful comment, and I agree with you that there is a significant need across practices to properly interpret the molecular testing that takes place either in commercial labs or in academic labs like yours. Do you want to comment a bit more about the structure of the molecular tumor board that we have at the University of Washington that you are leading and how this has clinical practice implications that could be modeled in other clinical settings and institutions as well?

Colin Pritchard: Sure, Petros. Yeah, so we've been doing a GU molecular tumor board since 2013 at the University of Washington and Seattle Cancer Care Alliance. So gosh, going on seven years now, meets monthly, very well attended, very highly successful. So, what we do is we mostly discuss genetic testing results that are done primarily within our academic center on primarily prostate cancer patients attended by, as Petrus mentioned, I run it, but it's attended widely by GU medical oncologists, also urologists, sometimes radiology, radiation oncology, and anatomic pathology. And so we discuss the tumor and germline findings of our patients, and it's very rich because we get to sort of dig into some back and forth and what it means for the individual patient. Of course, the same result doesn't mean the same thing, depending on what's happening with the patient.

That's part of the limitation, I think, of a commercial lab-only model. How can the lab know what the right result is when the result is completely dependent on what's happening with the patient? And sometimes the actual interpretation of that data depends on that. It's not just sort of looking at the report, but actually the interpretation of the raw data. So we dig into those details, we enroll patients in clinical trials, we make a lot of discoveries. So in the course of routine, maybe not routine, but in the course of advanced sort of genetic testing that we do, we've made lots and lots of interesting research discoveries and it's been very productive academically. It's also just a great way to get the teams together in a multidisciplinary way and really kind of build-up that program dynamic.

So, very much strongly encourage other institutions who aren't are already doing a GU molecular tumor board to consider it, and really reach out to your molecular pathologist colleague and get them involved. If they don't have the bandwidth to lead it, at least to try to get their involvement because it can be a very helpful person to have or persons to have to really explain what the results mean from the testing side.

Alicia Morgans: Great. It's so interesting and important to hear about how you do that. And actually there was a recent publication looking into whether molecular tumor boards could be helpful. Petros, I wonder if you could comment on the findings of that particular paper.

Petros Grivas: Thanks, Alicia. I think it's a very relevant topic as you mention. And as Colin said, we all struggle to have a timely review of those molecular testing reports have come in different patients. We did a study when I was back at the Cleveland Clinic, then we looked at what I called an expert review by genetic counselors and/or geneticists of somatic mutation testing, somatic genomic profiling, done by a commercial vendor in a molecular tumor board with the intent to identify any hints, sort of speaking, of germline mutations that can be present in a somatic mutation report, somatic genomic profiling report, to be precise. And see whether those patients who may not otherwise meet criteria for genetic counseling, they could be referred to genetic counseling services because of those hints or suspicion of germline variants identified in this somatic genomic profiling reports.

And interestingly, in that study, it was a retrospective study at the Cleveland Clinic, I think we were impressed because we found germline variants that were again hidden, sort of speaking, in these somatic genomic filing reports, and were able to identify a number of patients who otherwise would not meet criteria for genetic counseling. And we referred them to proper genetic counseling services, and they were offered proper designated and dedicated germline testing, which is separate on somatic testing. And those patients were found to have germline mutations and that was important in order to not only inform the patients in terms of treatment implications and clinical trials, so on and so forth, but also cascade testing and family member testing that can benefit the broader family. So, I think this is a very important thing, and in my opinion, there is an opportunity in multiple centers to do that. Obviously, it requires the counselors and genetic experts to do that. I don't know if, Heather, you want to comment on this and Colin since we've tried to do something similar to the University of Washington.

Heather Cheng: I'll say a few words about that. So, I think that what Petros was describing is very important with respect to the intersection of germline and somatic testing, and I think increasingly, especially in advanced prostate cancer, as we now have FDA approvals of rucaparib and olaparib, that this is only going to increase in terms of the urgency of thinking about how we do this properly. So, every institution and clinic or practice will have different resources. And we're so fortunate, as Colin was describing, to have our molecular tumor board, and in Seattle, at the Seattle Cancer Care Alliance, we also have the Prostate Cancer Genetics Clinic, which we launched in 2016, really in response to recognizing that this urgency was going to be there. And so to help serve patients who are undergoing testing or who have already had either genetic testing for cancer risk assessment and/or tumor, essentially like biomarker testing for clinical trial enrollment, that this was becoming much more complicated, but is no less important because we want to get it right.

And when there is an inherited component, as Petros was saying, we want to get our genetic counselors involved early, and like critical moments. But we also recognize as a field, I think that genetic counselors are highly sought-after, have very important expertise, but there are not enough of them. And so, we do need to find ways systematically to try to make sure that patients get the appropriate care and that we are triaging the efforts of our genetic counselors.

So, it might be a nice opportunity to showcase a recent publication from the Prostate Cancer Clinical Trials Consortium Germline Genetics Working Group, that was really led by two extremely talented genetic counselors, one at Alicia Morgans' institution, Brittany Szymaniak, and Lauren Facchini, who's at Seattle Cancer Care Alliance, and they're both genetic counselors who have expertise in prostate cancer. And they led this effort together with Dr. Rana McKay and Dr. Alicia Morgans who's on, and many others, to map out some of the critical needs that we as providers should be thinking about when ordering genetic testing. And one of the key points is really partnering with your genetics colleagues and clinical molecular pathologists, for example, to really make the systems robust. And so maybe I'll stop there, but I'll refer you to that publication, which, will be published in the Journal of Oncology Practice.

Alicia Morgans: Yeah, I thank you so much for mentioning that Heather because I think that was a great example of a partnership between the expertise of the genetic counselors and the clinicians who care for these patients. And we specifically focused on prostate cancer in that paper, but I think that the lessons learned and the things that were discussed could be extrapolated to other cancer sites. And I also, of course, appreciate that you lead that Germline Genetics Working Group. And I'm so grateful that you've actually had us put together multiple publications related to identifying barriers, giving overall recommendations on including germline testing in prostate cancer care. And then certainly this latest paper, just to mention that the paper gives guidance on how different practices might be able to incorporate germline genetic testing into their practices, and we know that every practice is different. And certainly, this is something that needs to be considered both by urologists and medical oncologists, which inherently have different flows to their practices.

And so we tried to give guidance that could be applied in different settings, recognizing that there will be no one-size-fits-all answer and that sometimes we need to call on folks outside of our own practices to help us implement these things, which we know are necessary and useful for patient care. And just to throw it back to you, Dr. Cheng, one of the things we touched on was that we don't all have programs like you have at the University of Washington, and you lead a very successful program and certainly partner with your molecular diagnostics partners in pathology. But for folks who don't have that, is there a way to reach out to folks at the University of Washington? And, other than that, besides that, if you want to stay on your own practice, how might you implement some of this guidance, if you don't have a genetic counselor say, for example?

Heather Cheng: Yeah, thank you. So, I think that we are a consulting service, and so we can, for example, see patients' second opinion and welcome them to the Prostate Cancer Genetics Clinic and/or we're building up our capacity to be able to do our molecular tumor boards on a consult-type of service for patients in other locations. And this may be true for other institutions as well, that are more high volume. And so we certainly welcome any communication or referral, and we are developing and building those programs at the University of Washington and Seattle Cancer Care Alliance, but then sort of to answer your question about broadly speaking, there are telemedicine programs and there are, I think in other centers, high volume centers of excellence, increasing awareness that molecular tumor boards are very important and require a multidisciplinary partnership to really do it as well as we possibly can for our patients.

And this really necessitates genetic counseling for cascade testing to really be able to maximize the benefit. If we do find an inherited cancer risk mutation, then there are life-saving implications for relatives, so we want to make sure that the relatives have access to that, and as a medical oncologist, thinking about PARP inhibitors or immune checkpoint inhibitors that may have patients who have underlying germline cancer risk mutations. So, all of this is very exciting but really requires a multidisciplinary effort. And so if that doesn't exist, there are resources available here in Seattle at the University of Washington and Seattle Cancer Care Alliance, but also perhaps in your tertiary centers, cancer centers near you.

Petros Grivas: Heather, I thank you for this detailed response. I think it's important to give you a shout out for this huge effort with the GENTleMEN study that you are leading, which is a statewide effort trying to pretty much offer at no cost genetic testing, germline testing specifically, using a commercially available assay, and then offer remote genetic counseling in patients with a variance of unknown significance that requires a genetic counseling or pathogenic variance. And I think these are great efforts, but in my opinion, should be modeled in other areas as well. Even though you have a comment on that briefly, and then I have a question for Colin after that.

Heather Cheng: Sure, thank you, Petros, for that mention. So yes, so that study is the GENTleMEN study, and in fact, it's now nationwide, so it is available for patients who have metastatic prostate cancer anywhere in the United States. It is web-based and phone-based, so if patients live in a more remote location, they can still participate. It's patient-driven, they go to the website, which is www.gentlemen, with an 'e,' study.org. And they can learn about the study and participate, and they are mailed a saliva-based test kit that they can complete and then have telephone-based genetic counseling, which is intended as I should say, not to replace existing genetics capacity and services at local clinic practices, for example, but to supplement, in the event that there isn't access or there's a high out-of-pocket copay. That's the reason for this study, and so it is a nice opportunity for patients who might be interested or are...

Petros Grivas: Thank you, Heather, I agree with you, and I have personally many patients who benefited from that effort, and thank you for leading this. If I can ask Colin quickly, I know Colin, we have discussed about prostate cancer and the reason if the approval of two PARP inhibitors in the metastatic castration-resistant disease. Can I ask you, how do you utilize, or do you envision programmatically care pathways utilizing genomic testing, somatic and/or germline, which is separate, sometimes integrated into some assays in workflows so we can translate results into clinical practice?

Colin Pritchard: Yeah, thanks for that question Petros, it's a nice follow-up of that great discussion Dr. Cheng had on the genetics issues and also the complexities around doing germline testing and somatic testing at the same time. So, I think we really are getting to the era where we need to be thinking about doing testing, both the germline and the tumor really upfront, and really getting to an era where we're not even really thinking of them as separate tests. I think where we're going as a field, given this recent approval of PARP inhibitors for prostate cancers, we need to be testing both, the approval is based on both germline and somatic, and importantly detecting the signatures of homologous recombination DNA repair deficiency, which is really the hallmark that is probably the important predictor of PARP inhibitors. That signature analysis is really optimally done with a paired tumor and germline sample. So, even from a technical standpoint, it's optimal to test both at once. And so if you're testing both at once, you might as well, also be doing the formal analysis of the germline, which is a criteria for the PARP and the tumor.

So, not to minimize the complexities around that, because of course, once you start talking about testing germline genetics upfront, and most are all men with metastatic prostate cancer at the same time as tumor, you need to think about the consents and, and how that works as a system. So, as you kind of indicated, I think thinking about pathways, thinking about how to get genetics, our medical genetics colleagues involved, genetic counselors involved, but also being pragmatic and practical about it as a system. I think we're... I heard a talk from Les Biesecker last year, who's the head of the NHGRI, himself a medical geneticist, that he called for the end of genetics exceptionalism. And, I'll try to summarize this point, but his point is, why do we put germline genetic testing in a separate box that's really kind of all on its own and different than other complex diagnostic tests? And this is coming from a medical geneticist and the head of the NHGRI. So he said, look, we got to get past that because it's so important for our patients.

So again, not to minimize that the counseling and consent issues are really important, but we also need to be pragmatic and practical about it and sort of weigh that we don't want to go too far on the side of barriers to getting this really important testing done. And so, again, like you mentioned, that's where pathways come in, and we're excited to sort of implement pathways through your leadership, and others, and Heather, and of course myself, we're involved at the University of Washington, Seattle Cancer Care Alliance, so that we can facilitate this. But I think it's a great model so that everybody's on the same page, everyone understands what's going to happen, how the patients are going to be consented, what's going to happen when you get a positive germline result, et cetera, et cetera.

Alicia Morgans: Great, thank you so much. I am so appreciative of your time today, and I think it's amazing the distance that we've covered in such a short time. And, of course, the things that we have yet to discover, and the things that we have yet to implement in our daily practices. But I so appreciate all of you for your time and for reviewing these aspects of genetic and genomic testing and the use of these results in GU oncology. Thank you.