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Alicia Morgans: Hi, I'm so excited to be here with Professor Bruce Montgomery, who is joining me from Seattle to talk about some work that's being done in genetics in the Million Veterans Program and where we go after that. Thank you so much for joining me.

Bruce Montgomery: Thank you for the opportunity to talk about this. It's really important and I think it's a topic that is going to become even more important in the years to come for a number of reasons. So if you don't mind, I'll just launch right into it. So what we were doing is what's called germline testing or germline sequencing. And germline testing is looking at normal DNA to see whether somebody inherited a predisposition to get cancer. And we're talking about prostate cancer today, but this is something that it's already indicated in breast, ovarian, pancreatic cancer. Very soon I think we're going to be doing this across all malignancies for patients with advanced disease because somewhere between 10 and 15% of everybody who has advanced cancers of any type have inherited a predisposition of some kind. So although we have very specific subsets of patients today, like metastatic prostate cancer that we are supposed to be doing this for, it is eventually going to be something, what we are doing in this project is going to be relevant to everybody.

So I think it's important just to know what germline testing is about. So germline DNA is the DNA you and I inherited from our mother and father. And in some subset of people there's a gene that doesn't work particularly well that they inherited. And because everybody inherits two copies of the gene, if one of them doesn't work well then the overall ability to do things like repair DNA damage is partly compromised. And so that's the first step towards getting cancer. And so in prostate cancer, specifically, if you inherited one of these genes, that doesn't work very well, it oftentimes is what leads to you getting a diagnosis of prostate cancer. Now that is obviously not what anybody wants. On the other hand, it is also an Achilles heel for the cancer, right? So because the cancer developed, because the cells can't repair DNA damage, but if both copies of that gene are knocked out, then it can't repair DNA damage that you're inducing in it.

So what's called targeted therapy, things like PARP inhibitors or platinum agents, it can't repair that DNA and people have the potential for exceptional responses. And the other thing is immunotherapy. For example, people who have inherited what's called a Lynch gene, so something that predisposes people to things like colon cancer and prostate cancer is in that spectrum. Immunotherapy can actually be curative. So finding these patients who have Lynch genes is also really critical. So part of why we do it is because we then can provide better therapy for patients. The other part, which is equally important really, is the fact that if somebody inherits one of these genes, then anybody related to them by blood has a significant chance of having inherited it as well. And many of the families that have this gene are not aware of it. I mean, there were a number of presentations at this meeting ASCO, where people were talking about the fact that anywhere from half to three quarters of the families that turned out to carry these genes were unaware of it and did not have any idea.

And the idea being that if somebody hasn't had a diagnosis of cancer but has one of these genes, there are some very effective modalities that can be brought to bear, prophylactic things like medications or operations or whatever to prevent the cancer. Or you can just surveil it very carefully and catch it at an early stage, which then allows you to cure the disease and prevent it from becoming a problem down the road. So in the big picture, we're doing this for patients because they get better care and for their families, and it's a national recommendation for a number of different reasons.

Alicia Morgans: Absolutely. And I think you and your team presented some data from the Million Veterans Program from the VA system at ASCO 2024, and I would love to hear what you presented.

Bruce Montgomery: Well, thank you. So yeah, so we're obviously very happy to present this work. So the idea here was there is a group of folks in the VA who have contributed sort of to the greater good by just providing their genetic data in what's called the Million Veteran Program. It's actually sort of a precursor to All of Us, which is also an NIH program doing the same thing. And because we actually knew a lot about those men, we actually said, well, let's pilot this study looking at trying to reach out to them and see if they would be willing to have testing done. And so we could tell who had metastatic prostate cancer. We sent them just a letter saying, if you don't want us to approach you about this, let us know and you can opt out. If we didn't hear from them, we sent them more information about what germline testing is, the pros and cons of it.

And then we would call them and say, are you interested? And we would get verbal consent. So it wasn't written consent, but verbal consent is adequate for this. And then we would send them a saliva kit in the mail so we could reach anybody anywhere and have them do the saliva kit at home. They would send it back, we would get the result, and if there was some either positive or negative, we would send the result directly to the person who participated and their provider. And if they had a pathogenic, what's called a pathogenic variant, an abnormal gene that predisposed them to getting cancer, they had the opportunity to get what's called post-test counseling, talking about how to approach this, how to let people in their family know about it, how to get them tested. In fact, that was actually part of the study as well, is we were going to do facilitated testing of the first-degree relatives as well.

And so at the end of the day, we approached about 2000 veterans who had metastatic disease, and of them about 25% completed the testing. Now, that is not what we want. We want 100% of people to get tested. But in the United States today, both in and out of the VA, the testing rate is about 10%. So using letters, one coordinator's time, half of a genetic counselor's time, we were able to get 25% of those patients to get testing done, which that's something that has some advantages because you don't have to live next to the medical center. We can send information and call people essentially anywhere. So that has ramifications for people who live in rural areas, people that don't otherwise have access to care in a number of ways. So we were actually pretty excited about that and think it's a potential approach for the future.

Alicia Morgans: Absolutely. And so speaking of the future, where do you go from here with this work?

Bruce Montgomery: Yeah, it's a great question. So I think a lot of people are interested in how we can change this. I mean, there are many aspects of genetic testing that I think we're all interested in improving. So part of it is access. There are also parts that people need to be fully informed and aware of the pros and the cons. And so making sure that people are as aware of the advantages and disadvantages as possible because somebody who's educated is better able to advocate for themselves. So what we're going to be doing mostly within the VA, because there are some advantages there in terms of the ability to centralize therapy and costs and everything else. We're going to be looking at the standard point-of-care approach, which is what is happening most of the time where a patient sees somebody in clinic, they have a conversation about the pros and cons in testing. They get consent if they want to participate, they send them down to the lab and get testing.

So we're going to compare that approach, which is the one where we're right now not doing quite so well to this remote approach. And then after a certain period of time, depending on whether they do or don't elect to get tested in either group, then they're going to cross over. And so the idea is we will cover the whole VA, rural and non-rural veterans with the opportunity to get tested if they want to. And I think that that's something that, the main thing is giving access to people. And I think one of the takeaways is one, we can reach most people where they are. The other thing is what was also interesting is that across the various groups of people, ethnicities and races and everything else, there was pretty equivalent uptake of testing. Didn't really matter who you were or where you were, people were interested in genetic testing. And sometimes I think as providers we're a little too sensitized about whether people should or shouldn't get tested. And I think we're going to be able to address that in a number of different ways.

Alicia Morgans: That's so important, especially I think in a veteran's population. I wonder if you see any way that this might be applied in a larger patient population beyond the VA?

Bruce Montgomery: Yeah, that's really the big question because we do need to reach everybody. Right. And I think that the advantage of the VA system is that they have a centralized electronic medical record, and the data is centralized. So we can access that and we can tell whether people are appropriate for being tested. I think this approach could definitely be used more broadly. I think it would be a little more complicated because all of the electronic medical records and those sorts of things are a little bit more disparate. But I think it definitely has the potential to be used across the US and even outside of the US. There's no reason that this has to be limited to one country.

Alicia Morgans: Wonderful. So what is your final message for folks as they're thinking about this program?

Bruce Montgomery: Yeah, again, I'm biased, but I think there are a lot of reasons why people should get germline testing. And I think it's worthwhile emphasizing that it is recommended that men with metastatic disease have testing of their tumor. It's called somatic testing, and get germline testing because we actually know that it's really important people have testing results from the testing of the tumor, which suggests they carry these alterations. And if it doesn't get followed up, if they don't get the testing done, their families never learn that they could benefit from this information. So I think the main message is for providers, it is in the patient's best interest, your patient's best interest to be doing germline testing in addition to somatic testing. Testing period is critical. So doing testing is recommended for everyone. And for the folks who are actually dealing with metastatic prostate cancer, they should really look into, if they haven't been approached to get testing done, they should ask their providers if there's a reason why they shouldn't. And I think at the end of the day, we want everybody to have the opportunity to get the best therapy possible.

Alicia Morgans: Well, I don't think that anyone could agree more. So thank you so much for continuing this work, working on a particularly important population of individuals who have served their country and who now need us to really serve them in this way. And I so appreciate that you took the time to share the way in which your team is working towards a brighter outcome for these patients. Thank you.

Bruce Montgomery: Thank you for giving us the opportunity to talk to people about this. Much appreciated.