16 – Understanding BRCA Mutations and Hereditary Cancer Risk – Part 1
January 16, 2024

Krissa Smith, Vice President of Mission Partnerships at Susan G. Komen, joins us to discuss the complexities of the BRCA gene and its impact on hereditary cancer risk. Krissa shares her family’s experiences with genetic mutations, including the p53 gene, and explains the importance of genetic testing and how it can work in partnership with evolving cancer screening technology. Stay tuned for part 2 to learn more about genetics, cancer risk, and the importance of early detection.

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Kim 00:07
Welcome to The Cancer SIGNAL, a podcast presented by GRAIL, where we discuss the impact of early cancer detection, the science behind multi-cancer early detection and insight into how this approach has the potential to shift the cancer paradigm. I’m your host Kim Thiboldeaux. Joining us today is Krissa Smith. Krissa is Vice President of Mission Partnerships at Susan G. Komen. Komen’s mission is to save lives from breast cancer. Krissa’s passion is to ensure the patient voice is heard and met and does this by raising visibility for key patient priorities. Her decade of experience developing research strategies in breast cancer and working alongside patient advocates has provided a strong foundation in understanding patient needs and the research community. This passion stems from a personal family history of inherited cancer genetic mutation. Welcome to the show, Krissa.

Krissa 00:58
Thank you so much for having me, Kim, I am thrilled to be here. This work is so personal and important to me and those that I love. My goal is that no one goes through cancer alone, and that we really have a chance at solving this incredibly difficult problem.

Kim 01:13
Well, let’s jump in on our topic today, BRCA. Let’s start with some basics. Krissa, for our listeners, please tell us what is the BRCA gene? And what is it supposed to do for us when it’s operating normally?

Krissa 01:26
Great question. We often hear in the breast cancer community even beyond that, that somebody has BRCA. And it turns out that everyone, men, women, everyone has the BRCA gene, but it’s the mutations or changes in this gene that really cause trouble. BRCA stands for breast cancer genes, there are both one and two. They are two very closely related genes have a similar function, that when they’re working properly, it’s going to help prevent cancer. They do this through repairing damage to DNA. It’s incredible to me how our body has built in mechanisms to repair something like DNA.

Kim 02:03
So let’s jump in. So we all have BRCA. But then certain folks have what we’ll call a mutation. So how does a mutation in BRCA one or BRCA two impact one’s cancer risk? And what are the cancers for which a BRCA mutation elevates one’s risk for women, for men? Can you speak to that?

Krissa 02:25
Absolutely. So DNA damage, obviously, that can impact quite a few cancers. What most people have heard about is breast cancer with BRCA for women, but also for men. So for women, their risk goes up in breast cancer, ovarian cancer, pancreatic cancer, and melanoma. And in men, they also have an increased risk of prostate cancer. So this ends up being kind of important. And BRCA one and two, they act like skilled mechanics, when they fix that damaged DNA. When they are mutated, they no longer work and so that damaged DNA no longer gets repaired. And one mistake leads to more mistakes, eventually, the cell just starts dividing uncontrollably, which leads to growth. And that’s what is leading to cancer. So this gene plays an important role in keeping cancer at bay.

Kim 03:16
So Krissa, back in episode 10 of our of podcast, The Cancer SIGNAL, we discussed another genetic disorder, Lynch syndrome, which increases risk for several kinds of cancers. What do we know, how many genetic mutations are there? And how many that, you know, how many of us may be affected by these mutations? What we have learned about genetic mutations associated with cancer in the last 10, 20 years is extraordinary. And we continue to learn every day. But can you shed some light on that for us?

Krissa 03:46
Absolutely. So DNA is incredibly large. And if you think back to the Human Genome Project, and trying to sequence every single bit of DNA, and all of that DNA has the potential to be, have a change, be mutated and all of that, not all of that will lead to changes in proteins and functions that will lead to cancer. So when we talk about genetic predisposition to cancer, people are often really surprised to hear that family history is really important, but hereditary cancers that we know about with this specific gene causing or being responsible for elevated risk – that only counts for about 10% of all cancers, meaning that most people who develop cancer are not genetically predisposed. However, if you do fall into that category, like my family does, you have a 50% chance (Lynch syndrome is another example) of passing it on to your child, which can be really tough, so it ends up being a little bit more complicated than just one of your kids will get it, one of them won’t. If this impacts you, you really should talk to a genetic counselor who could dig into your personal risk and clarify this, and how this would impact you and your family.

Research is moving forward. There are some incredibly smart people working on this. We’re learning more every day about how family history is important to consider. There are some signs that may indicate that you should, that your cancer diagnosis within your family might be due to inherited gene mutation. So you might have, your family might have many cases of the same type of cancer, cancer might occur at a younger age, there might be more than one type of cancer in a single person. More than one childhood cancer, cancer occurring in many generations, your mom, your grandma, your great grandma all having breast cancer, or cancer occurring in both organs, like for example, having a primary breast cancer both in your left and right side, rather than having it spread. These are all things that are going to indicate that there’s something a little bit more going on there. And Komen has a free family history tool on our website that can help you visualize and record your family history to kind of get a feel for if that impacts you more than some, or maybe it doesn’t. And that’s great news.

We’ve had a few celebrities who had been very public about their BRCA mutations. Some more people have might have heard of BRCA, and its association with breast cancer. Lynch syndrome, as you mentioned, is caused by other mutations in DNA repair genes like mismatch repair, and Li-Fraumeni syndrome, which is caused by a mutation in p53. This one’s really personal to me, because this is this is the gene that’s mutated in my family. So one of the biggest advances in the last 10 to 20 years is that we now know of more gene mutations that can cause that increased risk of breast cancer beyond just the BRCA genes. So Komen’s About Breast Cancer site keeps a running list of all of these for breast cancer. So check it out, if you want to know more. Some of these genes are tested for in what are called multi-gene panels as part of genetic testing. And your provider can help you choose both the right panel and the right treatment options for you. And they might this, these multi-gene panels might also help inform your risk of additional cancers because some genes are not specific to just breast cancer or just the cancer that you thought you were learning about.

So back in the day, we couldn’t do anything other than keep an eye on you if you had a BRCA mutation, and hope that you didn’t get breast cancer. But another major advance that we’ve had in the past few years is that we now have treatment options that are tailored to people with a mutation. As of 2018, if you have a BRCA mutation, you now have the option of PARP inhibitors. It’s a really good treatment approach for people with a BRCA mutation. If you have an earlier stage breast cancer, it might also help you think through those options about mastectomy. That’s a big decision. If you have a BRCA gene like how, what are you going to do to try and prevent that? And how does that work for your plans for the future?

Kim 08:10
You mentioned a family history tool on the Komen site. What is that website? Where can folks find that tool Krissa?

Krissa 08:16
If you go to komen.org, or honestly, if you type in Komen and family history tool, that’s probably the fastest way to get there.

Kim 08:22
Great, great. We want to make sure that folks can get to these tools and use them. It’s amazing to hear about the scientific advances. Krissa, you know, you mentioned that your family carries a genetic mutation. And thanks for sharing that with our listeners, it’s really helpful. It’s called p53. It also increases the risk of cancer. Tell us more about this gene and how it’s impacted your family and what the family conversations have been like.

Krissa 08:50
Yeah, happy to share. Because this is really why I’m here. Having watched my family go through such challenges in dealing with cancer diagnosis over and over. It really has brought me to such an incredible place and patient advocacy and working to make things better for patients. So we mentioned earlier that p53, like BRCA, is important for DNA repair. It turns out to be really important. So p53 is the most common mutated gene in cancer, all cancers. Sometimes you’re born with a mutation like those in my family, and sometimes you acquire those as your DNA starts making all those mistakes. When it’s mutated, it can no longer act as a brake and stop the cells from growing, leads to this uncontrolled growth. And of course that isn’t ideal. This leads to cancer in multiple places in your body, often at a young age. So women who have Li-Fraumeni syndrome have a nearly 100% chance of developing breast cancer in their lifetime. And all with people who have Li-Fraumeni syndrome have a 90% chance of developing one or more types of cancer in their lifetime, and a 50% chance of developing cancer before age 30. Crazy, right?

Kim 10:04
Yeah, yeah, absolutely.

Krissa 10:06
Yeah. So it ends up being a big part of life. And genetic testing is a big part of that. So my dad has seven sisters, and of those seven sisters, he’s lost four of them before they turn 45. And most when they were younger, and that’s really why I’m here watching my family navigate the health system, which is not easy, even for people who, at this point, have a lot of experience with it. We have a lot of cousins who’ve lost their moms, just a real frustration with cancer in general, it really impacts family deeply doesn’t matter who you are, you’re gonna need help. And there are so many people out there who need additional help in order to get through it. So it becomes really important to be able to stand by people through that.

Kim 10:51
Well, I appreciate you sharing that about your family, because I think it’s just shedding light on this issue. And the importance of these conversations. You know, in families, especially as we’re, you know, coming up on the holidays, sitting around with our families, it’s a good time to maybe to talk about some of those family history issues and make sure we’re taking care of one another. Krissa, I want to just drill down a little bit more on genetic testing. Can you first for our listeners, break down the difference between genetic testing and cancer screening? When does someone need to consider genetic testing? What can they possibly learn from that testing? Versus when does someone undergo cancer screening?

Krissa 11:30
So really great question. And somewhere, I think that people do often kind of get confused, especially when doctors are talking really fast, or they think they’re getting one and they’re actually getting a different one. So cancer screenings are tests like a mammogram that’s recommended for the general population. So you don’t think you have breast cancer, there’s no pains, no symptoms, and there’s no real reason to get tested other than to try and catch something really early on. And of course, catching cancer early, it’s really important, that’s going to lead to better outcomes, better survival. That’s really the goal here is to catch those cancer diagnoses really early. Genetic testing is looking for changes that we call mutations in your DNA, BRCA is a good example. So just because you have a mutation and BRCA doesn’t mean that you have cancer right now, just means that you have a higher risk. So we have more and more genes that are being understood in the context of risk for people. So if you go get a genetic test that will tell you, if you have that mutation in the BRCA gene, or the p53. Don’t worry, they’re quite rare. So chances are you don’t have it. But if you have some reasons to think about it, you should go get it checked out.

Now who gets genetic testing is an entire discussion in of itself. There are people who strongly advocate that it’s beneficial for the entire population, especially as testing has gotten cheaper and more accessible. But right now generally, it’s recommended for people who have a few things that indicate it might be a good idea. So someone like me who they have several relatives with cancer, especially the same type of cancer. Also, like me, they might have a relative with a known cancer-causing gene mutation, p53. And again, like me, they have family members that had cancer at a very young age. If you haven’t had genetic testing, and you now have a cancer diagnosis, if you get genetic testing, you might be able to better understand the treatments that you can have. So there’s a couple of ways and reasons that you should do it. And you should talk to your doctor about that because they’ll be able to walk you through.

Kim 13:38
Okay. And while we have the attention of our listeners, should we remind folks when they should start getting a mammogram for the general population?

Krissa 13:44
Oh, we’re big fans of starting at 40. So please get screened. It’s always a great idea.

Kim 13:49
Excellent, good. Good. Always a good reminder for all of us. So focusing on BRCA for a minute, how is the mutation identified? Meaning, what kind of testing is done? To find out if you have BRCA? And I’m assuming if you do, then then your doctor may recommend different kinds of screenings than what’s recommended for the general population, correct?

Krissa 14:13
Absolutely. The more screening, the better. If you have these high risk genes, we could talk about that a little bit. In order to figure out if you have that mutation, because you can’t just assume, it requires a blood, a saliva, cheek cell sample, kind of like what they do on CSI. And they’re looking at your DNA just in the same way. But remember, a gene is made up of many, many pieces. And some of those, any of those pieces could be changed and cause a change in the protein. Some of our initial genetic testing really looked at the main changes, like five places where we were, oh, we knew that these would cause issues. Now they’re doing whole genome sequences where they’re really looking at every single base pair, every single part to see if you’re at risk. So, there’s also tests just for BRCA. But now they’re kind of shifting to these more expanded panels that are going to look at many genes. So you do one test for a whole bunch of genes, like we talked about listed on the website, if you want to take a look. Most of the time, you’re going to need an order from your doctor to get this done. There are some direct-to-consumer testing kits, which means they mail it to your house. Some of these are for looking at your like who you’re related to, things like that. They may also list for example, BRCA, but they’re not looking at every single base pair, they’re only looking at a few parts of that. So that’s not something you should really rely on for a medical diagnosis. So in general, we recommend any at home test needs to be confirmed with that clinically approved test, and a friendly genetic counselor. Speaking from experience, genetic testing, can have a really big impact, not just for you, but for your family, because you got that mutation from somewhere. And if you have that mutation, you can also share it with someone. So it’s important to really do this thoughtfully, understand what it means for you. And a genetic counselor is a really great place to start to, to think about how to do that.

Kim 16:22
And there are resources on your website to say who should get tested, meaning what level of risk, family history, etc., that would get folks getting tested? Is that correct?

Krissa 16:32
Yeah. And you know, it’s, you’re diagnosed at a early age, you’ve had male breast cancer that is rare. So chances are it might, it could be associated with BRCA, multiple cancers, all the things we were kind of talking about earlier. So take a look at that. See if you’re at risk. Those who are not diagnosed with breast cancer, one of the biggest things is if you know, a family member has a genetic mutation, that’s a really good indication.

Kim 16:59
Excellent, excellent, really good advice. Thank you. And I know we could spend a whole show just talking about all of those specific sort of risk factors, but talk to your doctor, look online, find the resources and potentially talk to a genetic counselor if some of that family history is there.

Hi listeners, my conversation with Krissa Smith continues in part two, which will be out soon. We will talk more about advancements in genetic testing, screening in those with cancer-related genetic mutations, family dynamics including hereditary risks, and much more. This is The Cancer SIGNAL presented by GRAIL. I’m Kim Thiboldeaux. As always, please rate and review our podcast, and be sure to subscribe as well.