Noor: Dr. Pederson, it's so nice to have you, Dr. Holly Pederson is a staff physician and director of medical breast services in the breast center. She's an associate professor at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. After receiving her BA in biochemistry from the University of California Santa Barbara, where she received the distinction of Phi Beta capta, Dr. Pederson earned her medical degree from the University of California San Francisco School of Medicine, where she was recognized in the Alpha Omega Alpha Honor society. She completed her internship and residency at the University of California, San Francisco Medical Center in Internal Medicine, and in 2008 completed a clinical fellowship in genomics at the Cleveland Clinic.

She directs the medical breast program and is active in clinical research. So Amazing bio. So nice to have you. What was your favorite part of training?

Dr. Pederson: Oh, that's a great, that's a great question. I was fortunate enough to spend both my medical school years and residency at UC San Francisco, and I just loved it there.

It was just a, a, an amazing environment, combining basic care often with a lot of immigrant populations with. High tech, tertiary care and VA hospital cares. I, I loved it though. That was my favorite.

Noor: I think your training happened during a really exciting time in genomics, obviously from 2000, all the funding spent to start the sequencing of the Human Genome Project to now.

So do you wanna, do you wanna start off by just giving us an overview of what is known about the genetics of breast cancer and how did we get here?

Dr. Pederson: That, that's such a simple question to answer. Yeah. Right off the bat. It it. Mendel was really the, the grandfather of genetics and noted the independent assortment of genes and pea plant reproduction.

And when I was in college, probably we mainly studied. That level of genetics in terms of what was known, it's now felt that probably most medical conditions and certainly many cancers are related to genetic, uh, abnormalities and the effects of genomics and the timeline has just been fascinating. In just a little over a course of my lifetime, we've really learned so incredibly much.

I think it was. 57 that, that, uh, Watson and Prick determined the helical structure of DNAI could be off and in 1994 and 1995. Um, BRCA one and BRCA two were identified as genes that can be implicated in hereditary cancer families. And I graduated from my residency in 1991 and worked for a while in primary care and then primary care women's health.

Started at the Cleveland Clinic in 1997. Two years after really the, the genes had been identified and started what we call now the medical breast program at the Cleveland Clinic where. We do diagnostics and follow long-term survivors, but we also do a lot of risk assessment advice around genetic counseling and management of patients at high risk.

Noor: How many genes are there that are currently known to, uh, increase risk or Yeah, that you're currently testing?

Dr. Pederson: So back in 1994 and 1995. Uh, the genes had to be sequenced one by one, uh, in a process called Sanger sequencing. That's very time intensive, expensive, laborious. And so back then when we did genetic testing, even when further genes were identified, um, there's probably 13 or or 14.

That are associated with breast cancer. Seven are very high risk and the others are more moderate risk. And we'll talk about what that means. But we used to have to choose which syndrome was most likely. And of course, BRCA is the most common hereditary syndrome associated with. Breast cancer, but there are others.

And so it would go in a one by one testing method and when next genera, next generation sequencing came out around the early two thousands, it just completely changed everything and allowed for. Testing of multiple genes simultaneously at lower cost and really made it more widely available. And then of course, later the testing market became competitive and many more companies became involved in next generation sequencing.

And it's available now even direct to consumer. The the next generation type, and I think it's important that consumers really realize that there's the next generation type and then there's a recreational, the recreational snip based type. Can over the counter testing, if you will, and one is extremely accurate and the other can be fraught with false positives and false negatives.

Really, the, the false negatives are mainly in the realm of genes that aren't tested for.

Noor: This is a really great point, but it's actually very technical. So could you just explain what is the difference between a gene. A variant and a spin.

Dr. Pederson: The DNA is an information coding system within your body that codes for proteins that perform functions in your cells.

It's really on a very simplistic view that simples abnormalities in the the type of protein that's produced or the function of that protein. Or it may just make it so that protein is not produced at all. In a cell. That's the idea of a genetic abnormality. And any change in the DNA is a mutation, and we now call mutations variants.

They just like to make it really confusing. There's also two different ways that they're written, and the same gene has different names entirely. It's tough, but the genes. Code for proteins. Abnormalities in the genes may affect the function of the protein or may make it so that the protein is not produced at all, and a variant is the same as a mutation.

When you're talking about. A change in DNA. It could be completely benign. I have blue eyes. You have brown eyes. It doesn't cause cancer, and we may have a different allele at that site and some genetic abnormalities are harmful. I. Those that are pathogenic or likely pathogenic. And then there's these variants of uncertain significance, which are changes in the DNA where we don't know whether it causes cancer or not.

And then there's like benign variants or benign polymorphisms. So that's what genes and variants are. And then you asked about SNPs. So there's three levels. Of genetic change that that predispose that either protects or predisposes a person to breast cancer. And the first are the highly penetrant genetic mutations.

Like BRCA one or BRCA two, those are the most common, but there are others P 10, P 53, pal B two. There's different, like a whole alphabet soup, but the But the highly penetrant gene mutations, I. We, the ones that were first discovered. And in those situations, the risk of getting breast cancer in one's lifetime is greater than not getting breast cancer.

And so that's a special situation. I. Then the moderate risk gene changes like check two and ATM are actually incredibly common in the population at large. One to 1.5% of of people of European descent carry mutations in check two or ATM, which again may or may not really increase their risk. Depending on other factors.

And then the third level of risk are these little, what we call snips. They're small changes in the genes whereby independently. They don't increase risk much or decrease it much. But when you combine all the SNPs together, and we now know of over 300 SNPs that are associated with breast cancer risk, if you combine them together in a weighted way, the effects of these SNPs can be important.

Whether you're a gene carrier in the highly penetrant or moderately penetrant group, it can sub stratify your risk. Or if you don't have a genetic mutation, it can help you have an idea where your risk is. That last thing I mentioned, that combination of the SNPs is called a polygenic risk score.

Ultimately, in my opinion, that might be helpful for everyone. For patients with family history, for patients without family history, but it's a a no brainer in terms of identifying people who may wanna be more vigilant about their screening program.

Noor: Yeah, that's really interesting. So I'm just gonna try to summarize all, all of that complexity.

Yeah, so basically like the way that you can think about a gene is, all right, there's a bunch of letters, A TCG, but there's a certain number of them. Let's say it's a thousand, 2000. Letters and they make up a gene. And if you have a gene and then you have a, basically this BRCA stands for breast cancer gene one B-B-R-C-A two, breast cancer gene two.

So if you have variants in these genes, it means you have a typo. You can think of it maybe as like a typo in this thousand or 10,000 letters. That's a good way to put it. In, in that gene. So those are the single gene causes that can radically increase your chance of breast cancer if you're in that high risk category or moderately increase your chance if it's in one of those moderate risk categories.

But basically the limitation of the array technology is that it's using a snp, that it's using a, just a single or small set of letters to try to proxy whether that gene or that pathogenic variant is present or not. But it's only able to detect a really small section, uh, or small fraction of those variants because there's.

Thousands of variants of any of these breast cancer genes. So you have to actually read every single letter of that gene to know, do you have a pathogenic variant or a benign variant of that gene? And if you're only looking at a few snips using an array technology, you're, you're then not able to detect and could give someone false certainty that, hey, you don't have a pathogenic variant because you don't have one of a very small number of pathogenic variants.

Dr. Pederson: Your explanation was excellent. And there are many people who don't, who may have a significant family history but are afraid to go in for genetic testing and don't want that in their chart, are afraid for insurance reasons. And, and that's very common. And uh, many of those people will turn to the recreational snip based testing that may tell them their.

Ethnicity and identify lost relatives. That's not uncommon. But also they're aiming to get genetic testing done for their breast cancer risk and. Really the three genes that are called founder mutations in the Ashkenazi population are the only mutations that are tested for in this test. And in the past we used to think that those three founder mutations accounted for.

Over 95 or 98% of the mutations seen in the Jewish community, but that's no longer the case. It's about 81% of the BRCA mutations are of that type, but there's a lot that are missed in the non-Jewish population. Those mutations are incredibly rare, and there could definitely be a different BRCA mutation or any of the other genes involved.

That could be playing a part in that family. And the way that the tests are marketed. PA patients don't really realize that's the case, that they're only being tested for those three Ashkenazi founder mutations, and it can be, I. Really important to, to talk to a genetic counselor or get some better advice on that front.

Many primary care doctors even, or OB-GYNs are not fully familiar with all the testing that's out there. And genetic counselors can be a really good source, I think.

Noor: So what do you think people should look for if they wanna get really high quality hereditary cancer testing? What are the key words that they should be looking for to find out is what I'm interested in actually going to be tested for?

Or am I gonna miss it?

Dr. Pederson: My opinion is really to get the opinion of a genetic counselor and talk to them about it. They're really the ones that interface directly with, uh, the different companies. They know the difference between the different tests, whether any additional genes. Need to be tested for in certain situations.

And, and genetic counseling can be done in person. It's usually covered by insurance. Um, some Medicare policies may not cover the counseling part, but they're, they'll cover the testing part. At Cleveland Clinic, the, the counseling is just comped to anyone who qualifies for testing. Um, but there's so many.

Things changing so rapidly that I think it's good not only to get advice on the front end, but on the back end. And so that does need to be done in person there. There are online resources available that are very good, and many of the reputable companies have genetic counselors that are employed by them.

If a patient does not wanna go the traditional route. Of an in-person genetic counselor. If they wanna do it in a more private way, they could interface with the genetic counselors that are employed by the company or by a telemedicine source. Yeah, those are some other ideas. That's

Noor: super. Yeah, that's a great idea.

Basically find out exactly what's relevant for you in terms of cancer. It sounds like you've talked about the monogenic side, and you've talked a little bit about the polygenic side. For the monogenic side. Can you just give like a a little bit of an estimate for. Who would you recommend get, get monogenic testing?

Do you have to have a family history to to get monogenic testing?

Dr. Pederson: Sure. So monogenic is obviously one gene. We're doing a broad panel of genes to be tested for in a particular family, some of which. Seem they're gonna turn out to be obvious, but others are a complete surprise. You can find genetic abnormalities that don't even match up with your family history and can really impact your screening.

Say there's something called Lynch syndrome, which is actually more common than BRCA even, and can be associated with very high colon cancer rates and people start. Colonoscopy screening even at the age of 20. So it's really wild. There are these multi-gene cancer panels, test for genetic changes that predispose to all of the known cancers that we are able to link the gene to.

And you really get a look at your risk for different types of cancer because they can be associated, say with BRCA one, you also have, with BRCA one, you have an estimated lifetime risk of about 70%. Same with BRCA two. There's a lower ovarian cancer risk with BRCA two. With BRCA one, it's about 44% estimated lifetime risk.

And with BRCA two, it's 17%. And like I said, all those highly penetrant genes have an estimated risk over 50%. And the moderate risk genes vary between 20 and 50%, and that's often influenced by that third level, that snip level, where you combine the SNPs in a weighted way and you get the polygenic risk score, which is the polygenic as compared to the monogenic type testing.

So when you get that multi-gene panel, you're getting the moderate and the highly penetrant gene. You have to seek out usually that. Polygenic piece separately, and that's not really mainstream yet. Mm-hmm. In fact, the National Comprehensive Cancer Network, which kind of evaluates all the literature, really suggests that at this time, polygenics might be best used in the research setting.

But in Europe it's being commonly used and patients are frequently making clinical decisions. Based on polygenics, which are available here, but there's a big education gap, both for patients and providers to learn more about that technology.

Noor: Yeah, so I guess when it comes to the polygenic side, can you explain a little bit more about that?

Dr. Pederson: Only about five to 10% of of patients with breast cancer are gonna turn out to have those highly penetrant gene mutations. Maybe another eight to 10% will have moderate risk gene mutations. And then there's everyone else that's, that's still a lot,

Noor: almost 15% right, single

Dr. Pederson: genes. 85% of the people say, I have this horrible family history.

Noor: Yeah, but

Dr. Pederson: my testing's

Noor: negative. Right? What

Dr. Pederson: do I

Noor: do? I think that's really interesting, right? So if you have, if you're negative for the monogenic testing, but you still have a family history. You still have increased risk, right? That's correct. It just means that you haven't identified. That

Dr. Pederson: is a huge point.

Thank you for Really, yes. Talk about that. Focusing on that, because a lot of people think, oh, I'm scot-free. I'm not at risk. And that's actually the most common situation is to be at risk from family history with negative genetic testing. And I'm caring for a family where. My patient's mother had breast cancer at an older age, uh, and.

My patient, the mother didn't wanna have testing. It was only indicated because she was of Ashkenazi descent, where there's a one in 40 chance of carrying one of those BRCA mutations. So my patient did the whole multi-gene panel, which was negative, which would've ruled out any abnormality from her mother's side.

And my patient's daughter has developed breast cancer at an early age with completely negative panel testing.

Noor: That's really important thing to understand. Basically, if you take a a recreational genetic test and you come out negative, that doesn't mean you're scot-free because you haven't got the clinical grade test.

If you take the clinical grade test and you're all negative, that still doesn't mean you have no genetic risk. It means that you don't have some of the most high penetrant or medium penetrants. But you still could measure your polygenic risk. And there's also people who are in the average risk for polygenic side who also have a very aggressive family history who are also missed.

I don't if you wanna talk a little bit more about, yeah, so, so

Dr. Pederson: here I am. I'm your typical person where the genetics are negative, but I have family history. So what we do is we combine often the effects of the polygenic risk score with breast density. And other traditional risk factors to sub stratify that risk.

And so everything's on a bell curve. Everything is on a bell curve. From weight to breast density to to bone density, to you name it. There's just people who are mainly cluster around the average. And then there's outliers that are either very high risk or. Supposedly very low risk. You know, we don't, we haven't had studies done to look at low risk patients to make sure that they're low risk yet, but presumably they will be.

Um, when you're talking about genetics and you're trying to sort out, am I in that 85% group or the 15% group. You wanna get genetic testing if you or anyone in your family had breast cancer at 50 or under in terms of age. And I wanted to mention also the laws that are in place that protect patients. Who are worried about having genetic testing?

Back in 2008, the Gene Law was placed the Genetic Information Non-Discrimination Act, which protects patients from discrimination in the workplace or with health insurance based on genetic information. And many states also have additional laws that. Add to that protection for patients. And really we in, in doing this since the beginning, I really have heard of very few issues in terms of, of legal or insurance problems.

Noor: Is, is pediatric cancer, like adult cancers, pediatric cancer, always genetic? What is the relationship between pediatric cancers and adult cancers? If there even

Dr. Pederson: is. Yeah. The way we view it. Uh, cancer shouldn't happen in a kid. It just shouldn't happen in a kid, and it's so devastating and we've leaned toward testing.

All children with with any type of cancer, just because it's not predicted for a child to get cancer. And when you look at rates of finding an abnormality in all comers under the age of 18 who present with any type of cancer, it's probably closer to 25% chance that they're going to exhibit some sort of genetic abnormality that's actionable.

LeRoi syndrome is, is probably one of the genetic abnormalities that, that we worry about the most when patients are identified with what we call a TP 53 mutation, and that can increase the risk of cancer. The cancer risks are very high, and the thing about the Lee Rahini is that. Between seven and 20% of patients who have LeRoi syndrome have what we call a de novo mutation, meaning it started in me.

I, my parents don't have this, this mutation. It started in either the egg or the sperm. The change happened and I'm the only one who has it and. There are families riddled with cancer where you feel like I'm next and then there are families with no cancer where all of a sudden you're identified with, with, uh, a syndrome like Lee Fra, which is incredibly rare.

One in 200,000 people or something like that. Um, people shouldn't. Worry about it unless there are signs of it, which are early onset breast cancer. There are, yeah, basically three breast cancer syndromes that will screen under 18 for not brca. We don't recommend screening for BRCA testing under the age of 18 because the cancers with BRCA tend to start around the age of.

30 and then go up from there. But with Lee Fra, they can occur in your teens with, and you're prone to all those other cancers as well.

Noor: So what can you do with this information? Some people are really afraid of, okay, I have a family history, I don't wanna talk about it, or, that was a really tragic situation in my life.

What are some of the benefits of having this information?

Dr. Pederson: Knowledge is power, and that's really what you wanna come back to, is that this could save your life and this could save the lives of your children. You've gotta be aware that there are. Choices that you can make to be proactive from enhanced screening, like getting MRIs added to your yearly regimen of doing mammograms and then alternating with breast MRIs.

You can get medications sometimes to reduce your risk, and we have those for breast cancer that are vastly underutilized and in patients who have that really high level of risk. Or moderate risk with a really strong family history or no genetic abnormality with a very strong family history. We even talk about risk reducing surgeries like mastectomy.

Is to help patients really reduce their risk by over 90%, probably closer to 95%. The medications reduce risk around 50%, and the enhanced screening of course, doesn't reduce risk, but it catches things earlier.

Noor: Do you think people without a family history should get tested either for the monogenic or for the polygenic risk or.

What do you think about that? Yeah,

Dr. Pederson: so first of all, people at people at average risk should know their breast density. They should start screening at the age of 40 and go every year. That is the current recommendation of the American College of Radiology and the National Comprehensive Cancer Center of which we are a part.

There are all sorts of guidelines. But 75% of women who get breast cancer don't have family history. So you know, you can't count on not having family history to go easy on your screening routine. In terms of genetic testing, I ideally you would want to test for the highly penetrant. And the moderately penetrant genes before you tested for the polygenic risk score, because you may not show family history if you choose to go down the.

Genetic testing route, probably both tests are indicated. Find out your density because there's supplemental tests that you can do for screening, even if you don't have a gene and, uh, and, you know, realize that you can get breast cancer without a family history.

Noor: And then in terms of the, the family planning perspective.

Let's say you find out a progenic finding, what can you do do with that information?

Dr. Pederson: Wow. I'm seeing more and more younger women interested in what we call assisted reproduction, and I, I need to explain it really carefully. So let's say you have a BRCA one mutation. We all have BRCA one genes in our family, and we have two copies of the BRCA one gene, one from our mom and one from our dad, and that's why you can still get BRCA one mutations from your father's side.

You should keep that in mind as well. So what the BRCA one gene does is it repairs DNA damage that happens on a daily basis to everybody. And so it goes around repairing the DNA in the cells. I. And if one copy of that BRCA one gene is mutated, it doesn't function, but the other copy still does its job.

Okay? So this is what a patient with BRCA one looks like. They have one healthy copy and one mutated copy of a gene, and they're either gonna pass down their good copy or their bad copy. In each pregnancy, their spouse or will presumably pass down a functional copy of the gene. And so each child has a 50 50 chance, whether it's mom or dad that carries the the mutated copy of the gene.

And so what you can do is actually test. Embryos very early in life to see if they carry the gene or don't carry the gene. Only embryos that don't carry a genetic abnormality are implanted into the woman's body to avoid passing on those genes to future generations. It's so exciting.

Noor: Yeah. And yeah, I think that the, what you were pointing out about Elif Ramini is also really interesting, right?

Is being able to look at those de novo mutations for the first time in embryos too, right? Because those are, again, definitive. We know they're going to be pretty. Pretty damaging and just having visibility into that so much sooner is just, it's just a cool thing to,

Dr. Pederson: and I'm so refreshed by hearing a young person be so open to all of the technology, and that's not the case as much in my generation.

And a lot of people don't understand or realize that this type of testing might be available or available soon. In terms of recommendations from. National organizations like NCCN?

Noor: Yeah.

Dr. Pederson: Yeah.

Noor: All right. So, so to close things out, what do you think is the biggest misconception for patients about cancer and genetics and for doctors about cancer and

Dr. Pederson: genetics?

Ooh, uh, the, this is on my feet. So what is the biggest misconception? The biggest misconception for patients is that if their genetic testing is negative. That they're okay and they don't need to worry if they have positive family history. So most breast cancer is not genetic and the most, the best person to test is the person who had the cancer.

'cause they're more likely to show the mutation. And so families need to know that. So I'd say that's the biggest misconception is that they go off and think that everything's okay because the testing was negative. And they'll learn that in, in estimating risk we use, still use the, the family history and the breast density and other things to make that decision.

I would say that providers, I would say not so much the misconception, but the lack of time. The lack of time, and lack of having a system in place in their office too. To catch those families that are more obvious. I think ultimately they'll all be interpreting polygenic risk reports, but at the present time, not even the highly penetrant genes are being caught.

Noor: So why is that? There's just not, there's just not enough time in the appointment. I

Dr. Pederson: think I would attribute it mostly to time, there's an educational component, but our primary care providers are just really getting over overextended during their day.

Noor: Yeah. So I guess what should patients do with that information?

Should they just advocate for themselves and say that, come in and say that they, they wanna get tested if they have a family history, or how, how do you think patients can help with that?

Dr. Pederson: Yeah, so patients need to advocate for themselves. Be an advocate for yourself, so, know. Your screening routine. If you're of average risk, start at 40 and go yearly and know your density and whether to get supplemental screening.

If you're at increased risk. Talk to your healthcare provider about MRI screening and about preventive medication, and if you're at really high risk. Anyone in the family with breast cancer at 50 or under triple negative disease, metastatic prostate cancer, pancreatic cancer, ovarian cancer at any age, multiple primary cancers, invasive lobular with a family, history of stomach cancer, all the things that we talked about.

Anybody of Ashkenazi ancestry with any type of cancer or even no cancer at all, is it's not unreasonable to test. And so take that knowledge into your own hands. Tell the provider, I think I need to go for genetic counseling. And if they say, oh, I think you're probably da, then. Keep going. Go find a different one or go online, go to a genetic counselor through a company or telemedicine.

Don't stop. If you feel like you might be at risk and try to get past that fear of going in for the testing,

Noor: what would you say to a patient who just feels afraid of getting the results? What would be your reassurance or, oh my gosh. I'm so glad you brought

Dr. Pederson: that up, because if you are a first degree relative.

Uh, and you haven't tested yet and your mom or mo mother, sister daughter had breast cancer and had or had caries A-B-R-C-A mutation. You can get MRI screening without testing. And you can start at age 25 and get MRI screening if you don't feel ready to test yet. So that's a really good point. Even if you don't feel ready to test, start going into the high risk center at 25.

Noor: Great. That's actually great advice. That's something very actionable. You don't even have to get over your fear. Just go do the other

Dr. Pederson: preventative. That's great. Exactly, because a lot of people go, when I get over my fear, I'll go in and start doing that stuff. But you can, it'll get covered. It'll get covered even if you don't test yet.

It's been a pleasure to talk with you. You're really, yeah.

Noor: Thank you so much. This was an amazing conversation. It was awesome to have. You. Have a good one. Well, thank you. Have a great day.