Are We Missing Patients? Expanding Germline Genetic Testing in Oncology

Dale Shepard, MD, PhD:

Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist and co-director of the Sarcoma Program at Cleveland Clinic. Today, I'm happy to be joined by Dr. Demitrios Dedousis, a genitourinary oncologist and cancer geneticist here at Cleveland Clinic. He's here today to talk to us about genetic testing. So welcome.

Demitrios Dedousis, MD:

Good to be here, Dale. Thanks for including me.

Dale Shepard, MD, PhD:

Absolutely. So, kind of gave a title sort of description of what you do here, but what do you do here at Cleveland Clinic?

Demitrios Dedousis, MD:

I have a few different functions. Most of my job is outpatient. I see patients who have certain kinds of cancer, specifically prostate cancer, kidney cancer, bladder cancer, testicular cancer, and take care of them and do their cancer treatments. But along with that, which is the traditional role of an oncologist, a cancer doctor, I also see people who do not have cancer but instead have gene changes that make them more likely to have cancers. Those are known as inherited cancer predisposition syndromes. And I do the extra surveillance that their gene changes justify to try and keep these patients healthy. So for instance, a man with a certain gene change, a BRCA2 gene change makes them more likely to have prostate cancer. You start your PSA screening at an earlier age than in the general population. I also, for a few weeks a year, take care of patients in the hospital who have cancer. Often, I'm working with the resident team and it's fun to work with the trainees and it's a way to get some education in.

Dale Shepard, MD, PhD:

Yeah, perfect. So, we're going to be talking about this genetic testing and there's a lot of different things when somebody says gene testing. Maybe we could just start at a really basic level because sometimes that means testing for a predisposition as you mentioned. Sometimes that means looking for family history and likelihood and kind of a similar thing. Sometimes we're talking about genomic testing of the tumor itself. Give us a little overview about, because sometimes people go, oh, I'm going to have gene testing. What all's involved with that and what are those categories?

Demitrios Dedousis, MD:

You're absolutely right about it. It's an ambiguous term. The first thing, if we're talking about the cancer genetics realm is we have to separate tumor or somatic genetic or genomic testing, which is to say we're testing, we're spell checking genes that are present only in the cancer or the tumor itself from germline or hereditary genetic testing where we're sequencing the genes that people inherit from their parents in most cases. And I'm really talking in this conversation about germline or inherited genetic testing. And this can be informed by family history and this is relevant towards people's other family, particularly their kids, because if somebody has a particular gene change, they have a one and two chance of passing that gene change down to children. So, it's relevant both to the patient and to their family.

Dale Shepard, MD, PhD:

So, if we talk about that sort of hereditary cancer testing, you're talking about cancer predisposition, talking to patients, how do these patients typically come to have the testing to either start seeing you or what starts that process generally? Who owns that?

Demitrios Dedousis, MD:

That's a great question because different institutions do it different ways. At the Cleveland Clinic, there are really two ways that people get cancer genetic testing and two ways that they come to me. One, if they have cancer before they're known to have a particular gene change and they meet certain criteria, it's now standard of care to do germline genetic testing in many people based on a cancer diagnosis. For instance, anyone with a pancreas cancer diagnosis qualifies for genetic testing. Anyone with metastatic prostate cancer diagnosis qualifies for germline genetic testing. The other way that I meet people and they get cancer genetic testing is they go through the genetic counselors. They're getting referred maybe by their primary care physician, maybe it's a patient self-referral, and often this is because of a family history of cancer. Someone knows that their mom and several of their sisters had breast cancer, or somebody has a dad that had prostate cancer at a young age or metastatic prostate cancer. So those can be people who are otherwise healthy that are getting their genes tested.

Dale Shepard, MD, PhD:

So, you mentioned that the diagnosis of many cancers will lead to a recommendation for germline testing, and NCCN guidelines now include that for a number of things. Is that one of the biggest things that has driven expansion is the sort of guideline recommendations?

Demitrios Dedousis, MD:

It absolutely is, and they keep expanding. Every year it feels like there's another indication for germline genetic testing. Whenever I see a patient, because I'm a genetics person, looking at their family history and looking at their personal history of cancer, is there a reason to justify genetic testing in this patient? And that's because often patients that are getting taken care of maybe by somebody who's not thinking about the germline genetics as much, many patients are actually getting missed in terms of having the standard of care genetic testing.

Again, I'm not talking about research, I'm not talking about pushing the envelope, I'm talking about bread-and-butter guideline directed genetic testing. It's also worth noting, and I do highlight this to patients because some patients say to me, "Well, I don't have any kids." Or some patients may be misunderstanding prostate cancer predisposition genes say, "Well, I only have daughters." And I explain to them, "Well, some of the genes that predispose towards prostate cancer also predisposed towards breast, ovarian and pancreas cancer, so it is relevant to your daughters, but it's also relevant to your health because if you progress through or your cancer rather progresses through the first few lines of treatment, if you find a gene change in particular genes, a homologous recombination repair pathway gene, there are several dozen of them, you actually can justify a PARP inhibitor like olaparib for a patient with metastatic prostate cancer.

So, I really highlight to patients that it affects their care, the care for their cancer, as well as the care for the people in their family.

Dale Shepard, MD, PhD:

As these guidelines are rolling out, and as you say, this keeps getting to be more and more of them, what do you estimate the adherence to that to be? I mean, how many people are truly getting the testing that's recommended?

Demitrios Dedousis, MD:

At the academic medical center at Cleveland Clinic here, in certain disease groups, I would say it's high. I think, for instance, this all came originally out of breast cancer. I feel like the breast cancer physicians are well versed in it, and not too many people are getting missed. I would say in the disease groups where the oncologists are not as comfortable with it, the adherence is rather low. And in the community, I suspect it's quite low. Often I see and I'm impressed that people come, and they get worked up, but usually it's when people are looking for another line of therapy rather than I try and do it right off the bat when I meet a new patient. If possible, I consent and discuss it unless they're overwhelmed. I find that often the first visit, sometimes the kids are there at the first visit is a good time to chat about it.

Dale Shepard, MD, PhD:

When we think about this cancer predisposition, how often are you seeing people, again, based on a diagnosis and then getting the guideline directed or testing rather, how often. We're doing more and more next generation sequencing of the tumors. Again, I know we're talking more about a person's germline, but more and more often we're getting somatic gene mutation testing, and that also could include germline. How often are you getting patients that just get picked up by the way with that testing?

Demitrios Dedousis, MD:

Incidentally found by somatic testing. It happens every week. I each week have a meeting. It's sort of like a tumor board, but for cancer genetics with the genetic counselors and other interested providers, it comes up every week. It's frequent. One of the telltale signs is if the variant allele frequency as it is at about 50%, that is to say the percentage of the genetic material that has that gene change is about 50%, that gets our antenna up for a germline gene change. If it's in the germline, it's going to be in the somatic two with certain exceptions. Whereas if it's in the somatic, it's not necessarily in the germline. Sometimes those labs flag it or if you send a normal sample like blood in addition to the tumor, sometimes they'll do the testing there as well to be able to confirm if it's germline gene change.

Others don't mention it. Our genetic counseling team, which is excellent, is very attentive to this and good at screening the somatic testing to find these and do the appropriate workup and follow-up testing if it's needed.

Dale Shepard, MD, PhD:

How often are you seeing patients who go to the local drugstore, they go online, and they get these genetic tests and send them away and then they're like, "What in the world does this mean?"

Demitrios Dedousis, MD:

It's not the majority by any means, but it's certainly something that's rising. And some labs that do direct to consumer testing are not very reputable. We often end up having to repeat the testing. Some labs claim to be able to do a whole genome, and we don't have confidence in it, so we meet them, and we say, "Well, these genes need to be tested, and we need to make sure they were actually tested properly." Often, we end up repeating the testing in that situation. Sometimes a gene change is found, and it ends up causing a cascade. You might easily in a big family find a dozen people that end up having a particular gene change, and that's known as cascade testing.

Dale Shepard, MD, PhD:

So, I guess can you give us an example of somebody comes to see you, they have a germline mutation, what that looks like in terms of making recommendations for either screening at that point or surveillance, or maybe give us an example of what might come from an appointment with you to discuss this.

Demitrios Dedousis, MD:

Sure thing. So, one of the most common gene changes that I encounter is a BRCA2 gene change. My practice is geared towards men who have a BRCA2 gene change because we have a breast center that's well established that has a very good protocol to take care of women that have a BRCA2 gene change. So, men with a BRCA2 gene change, it's justified to get a younger PSA screening. Some of that depends on the family history, the earliest prostate cancer that was identified in a patient's family. If a patient is 50 or greater years old with a BRCA2 gene change, it's justified to have pancreas screening to look into risk of pancreatic cancer. That can be either with an MRI of the pancreas or with endoscopic ultrasound. Many times, we alternate the two every other year under the theory that we're getting the best of both worlds.

There's not data that one is better than the other. I end up doing male breast exam and annual greater than age 35 and annual mammogram diagnostic, not a screening mammogram, always diagnostic in men at age greater than 50. And then there is some association with melanoma, although it's not a strong association, so we say it's an easy thing to do. Go ahead and establish with a dermatologist and get a once yearly skin exam. My practice is I meet with them, that's a lot of tests that I end up ordering. I meet with them again, maybe a virtual visit to go over it, and then we settle into, usually it ends up being a once-a-year rhythm to check a PSA or order the pancreas MRI. One area that's a relatively new area I wanted to touch on is that now for men that have a BRCA1 or BRCA2 gene change, it's in the NCCN guidelines, it's standard of care to offer a prostate MRI before the age of 50.

And that's because there was an Israeli study, about 180 patients that found in people with those gene changes, you catch a few extra cases by having a prostate MRI in addition to the PSA, the traditional PSA screening. Now, where's this going to go? It's not an annual prostate MRI, it's a one-time prostate MRI. It's nice to have a baseline. Let's say I meet somebody, they're 49, I get this test and they keep following with me for 10 years. Very rarely do you have a surveillance imaging that you only do once. I think this is an open area in the field, and we're going to have more guidance as we go on.

Dale Shepard, MD, PhD:

Are there plans to do any sort of testing or trials to see what that frequency might be, or is it just up to each individual physician discretion at this point?

Demitrios Dedousis, MD:

I would say right now it's up to each individual physician and it's a very new recommendation. I think it's in the last year or two here. So, it's where we have the first cohort of men that we are getting a prostate MRI on. I think one of the most useful things about having the prostate MRI when you meet the patient and establish with them is then as you're getting PSAs, if the PSA starts to rise, this day and age, we usually don't go straight to biopsy. We usually get a prostate MRI first to see if there's a targetable lesion. And having had the previously normal prostate MRI gives a nice baseline to see which lesion should be targeted. I have had one gentleman, we're waiting for a prostate biopsy, but there was a suspicious lesion that was identified with prostate MRI despite a normal PSA.

So that would be an interesting pickup if that turns out to be, God forbid, of course, prostate cancer. This is an open area in the field. I'm trying to develop a more protocolized high risk prostate cancer clinic or high risk... In other words, not high-risk prostate cancer, but high risk to get prostate cancer clinic where we have an agreed-on protocol on how to take care of these men with prostate MRI.

Dale Shepard, MD, PhD:

Structurally, how we do things here at the clinic, you're primarily seeing men with prostate cancer, the BRCA1, BRCA2s. Do you have colleagues and primarily focus on other disease groups or other predispositions to get other types of tumors? So, do we sort of segregate in that way? So, you have colleagues that might follow along for pancreas or breast or things like that?

Demitrios Dedousis, MD:

One of the things that I've been doing, and it's like a delightful Easter egg hunt, is to meet with everybody that's taking care of people with hereditary cancer syndromes. And we have some real gems at the clinic. We have the PTEN or Cowden Clinic, which is really in the genetics group and was led by Dr. Karas Ang, who was a giant in her field. That's a really interesting and useful resource. You also have the Weiss Center, which takes care of people with primarily hereditary predispositions to gastrointestinal cancers like Lynch syndrome and FAP, which is a polyposis syndrome. That also is an eminent center within that area. And then you have the breast center taking care of mostly women with increased risk of breast and ovarian cancer. That's not all people with germline predisposition. Some of that's family history based. And then you have the particular physician that's interested in an area.

We have Dr. Dhawan who's a neuro-oncologist that's interested in people with CNS tumor predisposition syndromes. I'm trying to meet with all of these people, so we know where to refer patients to as they're identified. For instance, we have a few providers that feel comfortable taking care of people with Li-Fraumeni syndrome, which is sort of the granddaddy of all the cancer predisposition syndromes. Women have a lifetime risk of something like 100% of getting malignancy over their lifetime because of the high risk of getting breast cancer. Those patients, and with certain other syndromes, end up getting, or it's recommended to get a whole body MRI. That's a lot to put on a PCP to just get the genetic testing and say, "Hey, now take care of this person." So, it's good to know who those providers are. I'm one of them in this case that can take care of people with those sorts of more complicated cancer syndromes.

Whereas someone with a reliable PCP follow-up could, after they meet me one-time, primary care could get the PSA at a younger age and refer them back to me or to urology if needed. Li-Fraumeni syndrome, I think that's too much to put on someone without specialty knowledge in this area.

Dale Shepard, MD, PhD:

Makes sense. How do you see the future? We have these sort of early ways to look for cancer, these early cancer detection tests, and just the field of doing genomics and testing is exploding. What do you see the world looking like in five years or so?

Demitrios Dedousis, MD:

One area that I'm especially interested in is multi-cancer early detection testing. We're in the early stages of planning a study to try and use some of these multi-cancer early detection panels. They're usually serum based. It's usually a blood draw in people with hereditary cancer predisposition syndromes under the theory that these people have a much higher pretest probability, they have a higher risk of having cancer to begin with. Surely this would be one of the populations that would benefit most from this testing if any population was going to. What we've come to is our first step would probably be to run some of these tests in people with a cancer predisposing gene change that already have cancer, because if our tests are not positive in those populations, they're not going to end up being very useful in any population. That's a project that we're in the planning stages on.

I hope that can become an adjunct to radiologic surveillance in cancer predisposition syndromes because it's difficult to have somebody get so many scans. It would be really nice if we could intersperse the scans with some blood tests. So, it remains to be seen how effective it'll be. Unfortunately, they're not as great right now at detecting some of the common cancers like breast cancer, prostate cancer, localized cancers. They're not as good at picking up, which is a challenge, but it's also an opportunity. I also see the other change I see in the field, and I think it's coming, I think it's inevitable, I suspect everybody with a cancer diagnosis of any kind is going to get both germline and somatic genetic testing at diagnosis. At institutions, there was one out of Memorial Sloan Kettering where they do this. They do germline testing, a panel of about 80 genes, a fairly standard panel these days.

In anybody with any cancer, you find a hit rate of about 25%. Some of these might be incidental, but a few studies have found something like that. That's not bad considering some of the more obscure tests that are part of our standard internal medicine workups, and it can be helpful to the family and often it can be helpful to the patient.

Dale Shepard, MD, PhD:

​Fantastic information. It would be wrong for me not to point out so people listening in can't see you. Love the bow tie with chromosomes on it, so very appropriate for today's discussion.

Demitrios Dedousis, MD:

Thanks very much. They gave this to me when I finished my genetics training, and whenever I have an excuse to wear it, I always break it out.

Dale Shepard, MD, PhD:

​Love it. Well, we spend a lot of time and energy. We talk a lot about treatments of cancers, but you're on the backside and you're looking to see how we catch things early by looking at predisposition, which is incredibly important. So, appreciate you being with us to provide your insights.

Demitrios Dedousis, MD:

It's what I'm passionate about. Thanks for the opportunity to chat about it.

Dale Shepard, MD, PhD:

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