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Neal Shore: Hi, everybody and welcome to UroToday and our online medical education program entitled Beyond Androgen Blockade, to New Pathways and Novel Treatments in MHSPC and MCRPC. I'm Neal Shore and I have the distinct pleasure and honor to moderate today's discussion following a presentation by my dear friend and colleague, Professor Elisabeth Heath from Karmanos Institute in Michigan. Her topic today is Germline and Somatic Testing Literacy.

So, thanks very much, Elisabeth.

Elisabeth Heath: Absolutely. Thanks for having me and I'm thrilled to be here to talk about this very important topic. So, the importance I think of the word testing literacy is just this area as you know, Neal, is just exploding all around us. Many companies, many testing platforms. And I think it's just really easy to get lost in the shuffle and we don't want folks to get overwhelmed or feel that the next test is going to be better when you're not really sure what it is that's happening.

So, I think taking some time to understand some of the definitions and some of the platforms that are being used would help us all in clinical practice. So, in just looking at the difference between germline and somatic, I think that's a big deal. We use these words all the time, but sometimes we don't explain it whether it's to ourselves or to our colleagues or even to patients. And so, they get roped into this conversation of, "I'm going to check your germline genetics. I'm going to check your somatic genetics for mutations." And understanding what separates the two I think is quite helpful.

So, in germline testing which is really looking at your inherited DNA, the germline DNA does not change over time. And it's important because you don't really need to repeat that test. So once it's done, it should be done forever. And it's also important to know that because sometimes your insurance won't cover that because they say, "Well, you've already had germline testing."

And the goal of germline testing is to identify risk for heritable cancers. And in our world of prostate cancer, that's becoming a very important point to understand as it might impact what kind of treatment a person could be offered. And importantly, all patients with pathogenic germline mutation should be referred to a genetic counselor.

It's not to say that you don't understand the results, it's just that the implications of those results can affect other family members that you will need help or assistance to be able to communicate the findings if that's what you so choose and get all of the important information from that professional, the genetic counselor.

We also will get in our results variant of unknown significance or VUS. And those should not be used to guide treatment. Sometimes we see that the gene BRCA2 which is what you're anticipating to look at is positive, but the positivity in terms of the language is variant of unknown significance. It's not pathogenic or likely pathogenic. So again important because you may unnecessarily worry your patient that their genetic mutation is going to be sent down to another generation. And the testing in germline can be done either by blood or looking at buccal cells from saliva. So, those are I think important highlights for germline.

Now, somatic testing is a little bit more broad. Some somatic tests, i.e., the DNA will have germline and additional acquired mutations. But it's important to know where you're ordering from because some of these testing platforms may not report that there is a germline mutation. So, sometimes we get lulled into the sense that, "Oh, well, yes, I have a metastatic prostate patient. And yes, I did order testing," but you're assuming that the somatic testing platform that was just ordered will tell you whether there's a germline mutation when perhaps that test is not geared to detect that.

The other difference is that while germline testing should pretty much be done once, you could repeat the somatic testing platform. So, perhaps when your patient progresses on the last treatment, you would like to know there are new acquired mutations to consider, so you would then repeat test. Sometimes it's a tissue test. Sometimes it's a blood test.

But just like in germline, the variant of unknown significance or VUS should not really be used to help guide treatment. And here, somatic testing can be either prostate tumor material so that's biopsies, surgical specimens, metastatic tissue or blood. So, important to recognize those differences.

The reason we test are many but in my practice, these three sort of areas really help I think articulate why you would want to order test. For germline testing, for sure, it's to better understand the personal and familial risk of cancer. It's also important to establish prognostic markers for aggressive disease and that would help you either establish the treatment plan and that would impact your decision-making at the current time or even for the future in terms of monitoring.

And then, to discover predictive biomarkers for novel treatments such as PARP inhibitors and other agents. So, ensuring that your patient will have the latest and greatest based on the testing, that again over time might change. So, in somatic testing world, repeat testing may discover a new genetic mutation that wasn't there several years before.

One of the things that's important is what is known as the red flags of hereditary cancer. There is a large list in the NCCN guidelines. And if you're looking at who are the folks that warning bells should go off when you talk to them, that would be good candidates for genetic testing, especially germline testing which is hereditary cancer evaluation.

These bullet points really highlight those at higher risk, so greater than two close relatives with the same cancer. So for example, a sister or two sisters with breast cancer in the same family. Greater than or two close relatives with related cancers. An early age onset of cancer, so less than 50, the 42-year-old with metastatic breast cancer or ovarian cancer.

Bilateral or multiple primary cancers, so the person himself or herself having more than one cancer. Triple-negative breast cancer. Rare cancer such as male breast cancer. Certain ethnic backgrounds like Ashkenazi Jewish. Abnormal tumor testing results so BRCA1 and 2 mutations perhaps that is seen in the somatic testing and you say, "Gee, I should make sure whether this is here in germline." And then new to this list is metastatic prostate cancer.

So, it's important to recognize this not just because we take a really detailed family history, but being able to take that family history and know what to do with it to enhance care not just for your patient but also for the next generation for that family.
So, when we're thinking about what is really inherited germline testing, what's that platform, and we've already talked about how it's different than somatic testing, most inherited germline testing uses next-generation sequencing technology or NGS for short. And here, the sequence analysis cover the clinically important regions of each gene. So, for example, BRCA1 and 2. And those include coding exons and 10 to 20 base pairs of adjacent and intronic sequence of either side of the coding exons in the specific transcripts.

And I think what that basically means is that there are certain genes that are already known in our literature and our current practice that are worrisome. And the ones that we're familiar with especially in prostate cancer or those in the breast cancer or DNA repair family. And understanding how that germline test will cover those areas is really important.

It also covers select non-coding variants. And most of these panels are about 84. Some will have 100 genes that are associated with hereditary cancers across major organ systems. So, not just BRCA1 and 2 but for example Lynch syndrome and so many others.

So, it's important to know that it's checking the most favorite 84 or 100 genes or whatever that particular platform is. But that also can change with time because as we get more data understood in our scientific world, that may change. And so, paying attention to the platform that you get your test, be aware that if there is a change in the upgrade or the downgrade of any particular gene, so for example, we just talked about variant of unknown significance or VUS sometimes can get upgraded to a likely pathogenic. You should get a notification and that then would be important and impactful for your patients in terms of what to do, in terms of action.

There's often confusion with the 23 and Me test. I've had patients say, "No, no, my doctor, you don't have to worry about it. I already did a genetic test. It's a 23 and Me." So, let's just talk about that. This is a test that many of us are familiar with. It uses saliva sample. And it's based on this understanding that the human DNA is 99.5% identical from person to person, but that there are small differences or variants in the DNA sequence that exists between two people.

And these variants are known as Single Nucleotide Polymorphisms or SNPs as sometimes you hear in conferences or that you read about. And the 23 and Me test focuses in on those locations in the genome that are known to differ between people.
So, the saliva processes the DNA that's on a genotype chip that reads hundreds of thousands of these variants in the genome. And the difference between this test and sort of true germline tests is that it looks at specific areas of the DNA. So, in general, this test does not report the risk for cancer.

Now, I know that these tests also can change and that there is some parts of this test that can detect some germline changes. But I think that there are dedicated tests to look at inherited or germline mutations that are probably more specific to interrogate that question than this particular test. So, just being mindful of the data.

And it's important here to recognize that sometimes your insurance company doesn't allow for full coverage or any coverage for these kinds of tests. And that's obviously a bigger topic than what today's discussion will be. But I want to highlight that there is an opportunity for our prostate cancer patients to enroll in a free registry called the Promise Registry. This is an observational study that is now available on prostatecancerpromise.org that will collect uniform data to evaluate germline testing outcomes for a particular population.

And you as a patient would establish an account, you would register, you would take an online survey, collect samples from the saliva, all for free, and get the information within six to eight weeks. And here, they're testing 30 genes with surveys.
Any patient with prostate cancer at any stage is eligible. There are some patients that don't have tissue diagnosis. So, if your PSA is greater than 100 or you have scans that show that you're also eligible. But I really encourage everyone listening today to visit this website because in this situation, you and your patient can actually go and understand and actually test for germline abnormalities in a free registry by enrolling.

And then you say, "Well, I've done all that. What am I going to do when the results are positive or I need to turn to a genetic counselor?" And this is really important because some health systems will have genetic counselors as part of their faculty and staff. So, check with your local hospital or health system nearby as they may have that resource.

But you may be listening to this talk today and not have that resource locally. There are national websites that can identify those resources for you. So, visit the National Society of Genetic Counselors, the American Board of Genetic Counseling. And for additional information, go on the National Cancer Institute website to be able to understand a little bit more about this.

And then just check also the resources. So, you tell your patient, "If your doctor has done this kind of test, then they also will probably offer genetic counseling services as part of that." Not every company does, but many will. So, it's really important to keep this particular resource handy so that you can have some help and also some resources for your patients in case those are not readily available to you.

And it's really important to talk about this topic now because we know it's not even ... Well, I guess it's now about eight years since this study was published that metastatic prostate cancer is biologically heterogeneous. So, by actually looking at all the samples and doing in a way a landscape of what's out there, you can see that many of the actionable mutations are ones that we were aware of like DNA repair and some that we have some drugs for and many that we don't.

And understanding that 23% of the mutations are identified in the DNA repair pathway is really and continues to be a game changer. And it's really important to know that understanding the mutations for your patients can actually result in an actionable next step.

And this study also recognized that 8% of the men had germline mutations. If you look at what type of germline mutations, you can see that the majority of our patients have BRCA2 as the main mutation at 44%. But you see all the other ones in this figure that may pop up in your report and understand that several of those will also qualify your patient to be able to be treated with a PARP inhibitor and understanding that it's more than just BRCA1 and 2 and ATM that the rest of them also allows you entry into considering a different class of drugs.

The word somatic molecular testing, again, batted about very loosely also uses next-generation sequencing technology or NGS. Here though, many of the companies are already testing your entire whole exome. So, we're kind of looking at 22,000 genes. Again, that's different than the inherited germline which is very specific looks at known genes ranging anywhere from 84 to 100.

Here in the somatic world, 22,000 genes and many of the testing platforms now are also providing whole transcriptome sequencing from RNA. So, that is a tremendous amount of information. And they also will provide genomic signatures like your HRD or homologous recombination deficiency or the loss of heterozygosity status, MSI, microsatellite instability or TMB, tumor mutational burden.

Some will actually give an HLA genotype, important because some clinical trials will actually use the HLA genotype as an eligibility criteria. So, recognizing that is important to enhance our awareness of trials and our eligibility requirements. And then, several of the testing platforms will also provide a protein analysis, whether it's to immunohistochemistry, CISH or FISH including mismatch repair.

So, in one particular test, you might get all of this information and many of them will provide all of this information. So, sometimes it's important to know everything. Sometimes it's just important to know some of the actionable, but all of this wealth of information should really be kept either in the medical record or given a copy to the patient with some words surrounding the, "You're not going to understand this test I barely do," which is what I often say. But at least it should be part of their medical record so that others in your multidisciplinary team can follow along.

One of the biggest areas especially in prostate cancer is understanding the DNA damage repair pathways. And I'm sure there will be another part of the Master Class Series that will really delve into this. But as we're thinking about germline and somatic testing, the DNA damage repair pathways is important because we have a better understanding of when your DNA undergoes some sort of hit or damage, how that will impact not only how the cell repairs itself but how then we can actually butt in with an agent to kind of disrupt that process even more.

So, if we look at the different types of ways that a DNA could be damaged, the one is single-strand breaks. So, this is where one part of your DNA is damaged and it uses PARP which is poly adenosine diphosphate ribose which is a protein that will repair that cell from that single-strand break. And it does so by using the pathway of base excision repair. And in a way, our goal of providing a PARP inhibitor is to basically stop the PARP protein from repairing the single-strand break.

Another way the damage can occur in a DNA in the cancer cell and/or regular cells is through a double-strand break. And at a double-strand break, you have two ways to try to fix it. One is homologous recombination repair which is HRR which also gets talked about a lot in our literature, in our discussions. And the other way is the non-homologous end joining.

And here, it's really important that there are several repair targets like ATR and ATM and DNA-PK. And those may sound familiar because those are now targets for a lot of the clinical trials and novel agents that are emerging in space. And then there are other ways that the cell can be damaged such as bulky adducts as well as nucleotide mutations. Leading repair way is through a mismatch repair. And in that sense, it's a whole other way to try to modify that repair pathway.

But it's really important that in our current world, understanding how PARP inhibitors really help to serve as an actual treatment is because of this particular path which is when you have a single-strand break and you now use a PARP inhibitor, you trap that PARP so that it prevents that DNA to repair itself because of that single-strand break that we just were talking about. And in doing so, it increases the double-strand breaks in the replicating cell.

And when you have that double-strand break, you either can repair it as we just chatted about by HRR or homologous recombination repair or in an HRD. So, if you are deficient in that, you can't repair it. So then, there goes. Now, you actually have cell death.

So, it's important to recognize, one, there is an actual deficiency that you just tested. And number two, there is a drug available. And in fact, there are many drugs available. And I put four here that have obtained FDA approvals starting with olaparib.
Here, olaparib was our first, actually technically by four days, our second FDA approval in 2020. And now just recently in May of this year is also approved in combination with abiraterone. And same with Niraparib in combination with abiraterone, talazoparib in combination with enzalutamide and then rucaparib as a single agent. And all of these are in-patients that have the HRR mutation or BRCA positivity.

So, not testing will lead to not being able to understand or be aware that your patient may be eligible for this new class of drugs, so very important. Also in that list, as I was mentioning earlier that in the report, all sorts of stuff including MSI status occurs. And here's another would-be missed opportunity if we didn't know which is that in 3% of prostate cancer, you can have an MSI high status of which pembrolizumab has gotten broad approval for solid tumors who have MSI high or MMR deficiency to be able to receive pembrolizumab.

So, I'm down to the last 3%. I don't want to miss anything that are available treatment options for patients. But you don't know if your patient is MSI high or MMR-deficient unless you check. And here is another reason that then we need to check.
I just want to end with this new concept that's emerging called minimal residual disease. This is also another type of genetic test. And the importance here is that we want to know whether there's any evidence of cancer rolling around, whether that's post-prostatectomy or post whatever surgical resection of the cancer or whether after treatment that you still have residual disease.

And the concept here is that the test uses different methods for whatever is the different platforms but you're looking at one cancer cell in one million healthy cells. So, it uses technology like flow cytometry, perhaps using samples from bone marrow cells or PCR which tries to expand the DNA to detect and count atypical genetic characteristics, or NGS again to examine the same. And it's to be clear that although this is a different type of testing, this asks a completely different question than what we were just reviewing.

So, in summary, I think there's a broad understanding that molecular diagnostics and technology is just growing at a crazy rapid rate in oncology. And it's really critical to understand the different testing platforms that are out there so that when you order the test for your patient, you know what you're getting and that you understand the results. Because understanding the results will help you be able to make the most appropriate recommendation for treatment so that if you're not testing, you're probably not offering the most up-to-date or relevant treatment.

The other point is recognizing that there are many red flags of hereditary cancer, metastatic prostate cancer being one of them. And there's a potential impact not just on your patient but on the patient's family members. So, to be much more broad in our thinking, it's really important to worry about your patient and also his family recognizing that these inherited cancers can be the gift that nobody wants that keeps on giving generation after generation.

And if you do discover one of these to leverage the professionals, the genetic counselors that are all around us for help, for yourself as the provider to also understand perhaps the genetic mutation but also for your patients and their families.

Neal Shore: Thanks very much, Elisabeth. That was a really exceptional overview. I appreciate your information that you were sharing about the importance of getting additional counseling in the community where there aren't a lot of certified genetic counselors. We tend to see them aggregate more in tertiary centers, large hospital systems. But in the community, they're hard to find. And 5,000 certified genetic counselors I've been told of which only half do oncologic counseling. The other half are doing infertility counseling.

And one thing I've seen in the community where you may not have that access, that commercial available companies, they all offer patients telehealth genetic counseling. And they all offer opportunities for family members to get free testing if a patient's already paid and has a PGV, a pathogenic variant.

So I think that's really good and I think that's really underutilized. But you know what? It was a great presentation, a lot of really wonderful content. I hope folks listening take advantage of going back and watching this multiple times. I'm fine saying that it's not about if you're going to do it, it's when you're going to do it. And you hammered home the important things.

But here are my two questions for you. One is from a patient perspective and the other is a physician perspective as to why we see this, quite unfortunately, a lot of underutilization in testing today in 2023. And I think that's one of the best things about this Master Class is your presentation.

I mean, I hear patients who will say even though their mother or father has a PGV, a germline PGV, they're like, "I don't want to know. I don't want to know." And I'm sure you see that. Now, let me just stop there. How do you respond to your patient who is BRCA2? It could be an HRR, any one of the other gene alterations, MUTYH. And they say, "I told my daughter, I told my son. They don't want to know." What do you say to that patient and their family members?

Elisabeth Heath: Yeah, that's actually ... I just had this discussion with a patient yesterday who has four siblings and he is a known BRCA. And he was very, very careful in articulating this message so that he wrote a letter so that there's no, "I said this to whatever. It didn't make sense." Nope, it's the same letter to all four siblings.

And the one sibling said, "Thank you very much for the information, but no thanks." No thanks like, "Yup, no thanks. I don't want to know for myself." And yet when my patient came back and said, "But you have four children, don't you want to know for them?" His answer was, "I totally understand. I've told them that you have this. I don't know for me. And if they wanted to do something about it that they could."

So, this patient's brother put it on the onus on his children and not on himself. And it didn't matter how many times the patient went back. So much so, he was almost sheepish and I said, "I don't think you could do anymore because then it ruins relationships." There are some people who just don't want to know.

Even though this could be lifesaving, even though this could be something you could do to prevent a problem, I don't think there's any words to overcome that, but I do know that when I focus in on what about your children or potentially grandchildren, patients are more receptive in engaging because maybe they're not so worried about themselves but they're a little bit more worried about what are they going to pass on.

I think the other part is recognizing, especially for prostate cancer, everybody thinks it's going to be like 100%. And it's really like 8% to 9% will have it as positive. So, they're understanding there's a high likelihood that it's not positive so that they feel like, "Okay, yes, I need to know but the odds are in my favor that I don't have this." So, getting that in there as a one-two punch is probably the best way that I can try to articulate it.

But we have a bigger problem. Forget the testing piece, Neal. I mean, there are many of my patients, I think many probably of yours that don't even want to know the family history, that they don't even go there because it's too complicated or their family hasn't talked about it which gives us a moment to say that typically during Thanksgiving, that's the moment to check your family history as the action item of as you're having Turkey and potatoes and stuffing, you talk about the things that are running in your families.

I think from a physician standpoint, it's sometimes quite hard to keep your mouth shut because you see this and you want to do something about it but it's just difficult.

Neal Shore: Yeah. Two quick comments and then I have my last question for you regarding the physician perception of testing. NCCN says germline testing right now in everyone, not just in metastatic, sensitive and resistant, if you're high-risk localized and you're Grade Group 3, 4, 5, do a germline test. Do a germline test if you're Grade Group 1, 2 with a significant family history.

Elisabeth Heath: Yup.

Neal Shore: The problem I have with that is, as you say and you're right, a significant percentage, some would even suggest 50% of patients are really not aware of an accurate family history, so there's a subjective problem even if you're Grade Group 1, 2.

And then it's all predicated upon the histopathology. If the pathologist gave you a Grade Group 2, maybe another pathologist would've given you a 4 plus 3, and even occasionally a 4 plus 4, which explains why myself and others are trying to just say, "Look, let's just make it universal." You've got a diagnosis of prostate cancer. Just like with breast, ovarian, pancreatic, colorectal, germline testing is the standard of care. The cost has come down dramatically.

My second question I had for you is physicians, and I hear this a lot amongst urologists, more so with your oncologists, but I even hear it with medical oncologists. I get these reports, they're really long, they're very detailed. They could be sometimes 10 to 20 pages long. It's a word salad soup of acronyms. "I just don't have the time. And some of my patients are worried if we get it, I'm going to stymie them regarding their insurances, especially on the commercial side." And I've even heard this at the Veterans Administration.

How do you respond to that physician who says, "It's just too overwhelming. I'm too busy." Where are we today in higher education for residents and fellows? I mean, this program is addressing the exact issue that I'm talking about.

Elisabeth Heath: Yup. No, I think it's a pervasive problem that we're chipping away slowly, but it needs to go faster. Part of the reason I bring up let's say the Promise Registry is that it's free and you have prostate cancer, boom, you're in. And do you know, Neal, that I have been telling all my patients this and sharing this with providers. It doesn't have to be docs, anybody on the team, and the uptake is still not great.

You have this free thing. Either it's not of high enough priority or no one understands the significance. I do see those 20 page reports. Usually, page one is the money slide but it really depends on which company you go with. And often, I'm sure you hear this too. It's like, "Well, that's great, Elisabeth, I'll get it but you don't come with the results." So, a lot of my colleagues will call me and say, "Do I have to worry about this? Do I have to worry about this?" Or a text like screenshot, no patient names but like, "Do I have to worry about this?"

So I think the education piece is also on the companies to really recognize that I know you want to give me everything related to the 22,000 genes and the millions of transcriptome data, but is there a way that you can just box that up to something much more manageable so that we concentrate on that and I don't get the 20-page reports?

I think there's probably some responsibility that needs to occur from the company level. And then, of course, for courses like this that you have to want to take the time to learn it. In our busy med-onc practice for the generalist, this is one patient in so many in a given day that you have to worry about the nuance. So, "Oh, is this the recommendation for breast cancer? What's the recommendation for lung cancer?" So you can't keep it straight. I think that's a major, major challenge that maybe AI will be our solution. That will be a flag and it will be automatic in EMRs. I don't know.

Neal Shore: Well, thank you very, very much, Elisabeth. A wonderful presentation as always and I'm sure a lot of our listeners will want to go back and listen to it over and over again. So, thank you so much for being part of this Master Class and great contribution. Really appreciate your expertise. Thanks very much.

Elisabeth Heath: Thanks for having me.