Melanie Cole, MS (Host): Welcome to the podcast series from the specialists at Penn Medicine. I'm Melanie Cole, and we have two specialists in Li-Fraumeni syndrome, one from Penn Medicine and one from the Children’s Hospital of Philadelphia. Joining me is Dr. Suzanne MacFarland, she's an Assistant Professor of Pediatrics in the Division of Oncology at CHOP; and Dr. Kara Maxwell, she's an Assistant Professor of Medicine in Hematology-Oncology from Penn Medicine.

Doctors, thank you so much for joining us today. Dr. Maxwell, I'd like to start with you. Li-Fraumeni syndrome is a heritable condition in which cancer risk is passed down from generation to generation. Which cancers are we talking about? Do we know what predisposes someone to Li-Fraumeni? Tell us a little bit about it and give us a bit of an overview.

Kara Maxwell, MD: Thank you so much, Melanie. Li-Fraumeni syndrome is a genetic disorder, and it's due to inherited pathogenic variants in the TP53 gene. P53 is the most commonly mutated gene in all of human cancer. So, about 50% of human cancers have mutations in this p53 gene. But unfortunately, a small proportion of the population, probably about one in 5,000 people inherit a mutation, or sometimes that mutation develops in embryogenesis due to a process called postzygotic mosaicism. And if an individual has a TP53 mutation in all of their cells in their DNA, they are at increased risk for a number of cancers. So, to kind of compare it to a syndrome that many, many, many more oncologists and the lay public are familiar with BRCA1 or 2, hereditary breast ovarian cancer, TP53, or Li-Fraumeni syndrome is just like that, just a bit more rare, and due to a different gene mutation.

If you have Li-Fraumeni Syndrome, there's approximately 90% risk of any kind of cancer over your lifetime. So, that's what makes the syndrome so devastating. It's a 20% risk of pediatric cancer, which Dr. MacFarland can go into in more details. In adults, the most common cancer we see is breast cancer. So, nearly all women who inherit a p53 mutation will develop breast cancer in their 20s to 30s. The median age is 32. We have women diagnosed as young as 18. After breast cancer, the syndrome is most commonly thought of, and for the docs that have learned about it in medical school ages ago, I remember when I learned it was a sarcoma-related syndrome. And so, we'll see any type of sarcoma, osteosarcoma, leiomyosarcoma, and other types of sarcoma. That's sort of the pathognomonic cancer associated with Li-Fraumeni syndrome. In addition, adrenocortical carcinoma, brain tumors, leukemias are all seen in this syndrome. Other very common ones include lung cancer, colon cancer, you know, and like I said, we've seen pretty much everything.

Melanie Cole, MS: Wow. Such an interesting topic. Dr. MacFarland, if the diagnosis based on genetic panel for TP53, what happens when someone tests positive for the gene? Tell us about patients, especially in the pediatric population when they have test positive. And a little bit about how that process works and how you approach counseling, genetic testing for individuals and families suspected of having this gene.

Suzanne MacFarland, MD: Yes, Melanie, that is a really excellent question. And you hit on some of the complex psychosocial dynamics that come into play. When you have a heritable condition that puts you at risk for cancer, that is so highly penetrant. Usually, when we have a patient who is suspected to have Li-Fraumeni syndrome and, usually, this is because of either their own cancer in childhood or a family history of cancer or sometimes we also pick this up based on the genetic testing of the tumor itself, we'll usually bring them into clinic and counsel them about doing germline testing and what that will mean for both the patient and then for downstream cascade testing of family members. That would be both parents and siblings.

Kara Maxwell, MD: I think that Dr. MacFarland hits on such an interesting point with finding the TP53 mutations now in tumors. I remember, in my PGY-2 year of Internal Medicine residency, we talked about a case at a conference and they said, "You'll never see this syndrome." But it turns out these syndromes are so much more common than we realized.

The tumor testing is one of those places that's been tough because TP53 mutations are common in tumors. And so then, you're trying to tease apart, is this one potentially germline or not? And places like CHOP do paired tumor normal testing. And it's been interesting, from that standpoint, because I'd say about 20, 25 years ago, if you brought this to many families where p53 syndrome was known in the family, there were studies that showed that over half of family members actually didn't want to get genetic testing. They didn't want to know that they had this. And that has significantly changed.

One of the most important messages that I hope to get out to other providers is that we can do so much more with early detection and screening. Dr. MacFarland and her team, are so good at talking to the families together. On the adult side, we see it from the flip side trying to help people decide about testing their children. And definitely, more and more people, with the awareness of genetics are wanting to get tested. But the point I guess I'm trying to make is that so much comes from us as providers encouraging our patients to know that this is something that we can have power over and do something about.

Suzanne MacFarland, MD: Dr. Maxwell, I agree with you completely on that point, and I think you brought up a important point about empowering our patients to undergo the testing because there is something we can do. There are really well-tested surveillance protocols that have been shown to improve survival in patients with Li-Fraumeni syndrome by detecting cancers earlier.

Melanie Cole, MS: Dr. Maxwell, what are the current recommendations for surveillance and management of individuals with Li-Fraumeni syndrome to detect that cancer early? And then, Dr. MacFarland, I'd like you to jump in with the psychosocial effects of this, this worry factor.

Kara Maxwell, MD: Of course, there's definitely no question that when we sit down with a new patient that, we're going to be talking to them about a pretty intensive cancer screening program. And I always start with saying, our goal is to find cancer at a surgical stage. So, as much as we have a lot of great medications in Oncology,if we can cure something by surgery, that is our goal to avoid those downstream effects of radiation and chemotherapy. In order to do that, we do do pretty intensive imaging-related surveillance and it changes over the lifetime.

So for children and adults, everybody, the backbone is a whole-body MRI. So, that's from tip of the head, depending on the age of the person down, all the way to their toes to look for the whole host of cancers. But particularly in kids, this is great for looking for sarcomas at a much, much earlier stage. Then, in addition in kids and Dr. MacFarland can expand on this, adrenocortical carcinoma being as common as it is in the syndrome, we add on frequent abdominal ultrasounds that help increase the frequency of looking for that cancer. And then, as kids become adults, it's a big transition. At 18, we're telling the young women, "We want you to be seeing a breast specialist at 20. We're going to start breast MRI." In young women with extremely dense breasts, MRI is really important for looking for lesions. So, we start that at age 20. When women get a little bit older and depending on the family history, we add in mammogram just to increase that frequency, given how common breast cancer is. And then, at age 25, we start doing upper endoscopy and colonoscopy screening as well, given that we're just seeing a lot of young colon cancer in our population in general.

And then, I always sort of say this is a backbone. We also do some blood work. Of course, physical exam's important. Skin exam is important. This will always be supplemented by additional testing. And that's definitely something that we try to get up front.

And I  think, talking to my patients, this all sounds so overwhelming. But once they get into a routine, they do feel that this is not incredibly cumbersome and they really understand the goal, like I said, to find cancers early.But I'll let Dr. MacFarland talk a little bit about the screening in kids because I know,that's obviously so much more of a challenge.

Suzanne MacFarland, MD: Thank you, Dr. Maxwell. There are additional considerations when we think about screening children. It is intensive, as you said. For children, we're checking in every three months with abdominal ultrasounds or whole-body MRI, the whole-body MRI being once a year and a brain MRI once a year. And we're trying to think about things like lifetime exposure to contrast, to lifetime exposure to anesthesia. So, we're trying to think through weighing the risks and the benefits.

And the other thing that you touched on, Melanie, was  the risks and benefits psychologically. Because we know that frequent screening and scanxiety and that stress can be difficult over many years, not just on the children, but also on their parents. You mentioned,  the siblings. We know that unaffected siblings, even if they don't have a diagnosis, are still going to be affected.And for those patients, as they exit the early pediatric period and enter adolescence and start to take over more control over their health, we want to make sure that they feel supported in doing their screening and understanding their health and understanding their syndrome. I think that's where we also rely on psychosocial supports in that team. And then, we rely on our patient advocates, like the Li-Fraumeni Syndrome Association, to really help us to provide those external supports in that community, given the rarity of this disease.

But there is so much to consider within that cancer screening in making it something that families and patients can continue with life long. And the other part of that is helping them to feel empowered and participating in things like research around Li-Fraumeni syndrome to make sure that we have patient-centered research programs to try to improve outcomes and I know that's something that Dr. Maxwell believes in very strongly as well.

Kara Maxwell, MD: Thanks, Dr. MacFarland. I think an important point is that the CHOP side of things are so good at trying to help the kid realize this is sort of the way my life goes as a kid, and I do these things and it's important, because we used to see a lot of drop-off, kids would be very intently screening because mom and dad would be bringing them. And then, they'd get sick of it and say, "I'm not going to do it." And, I will say, for the girls, that there was a little bit of difference there because they knew, "Okay, I've got breast screening. That's something common.I need to do that." But for our male patients, a lot of times there would be drop-off at the transition from pediatrics to adults. And that was the impetus for Dr. MacFarland and I to set up our program, to really try to help shepherd patients through, dropping off when they went from the children's hospital to the, more adult situation, And that's what's so amazing about these patients is that when we spend the time and, as Dr. MacFarland said, provide the psychosocial support, they really do feel empowered and they're very willing to come in and do all of this, screening.

And Dr. MacFarland just touched on the research, that's where this is all going. Early detection of cancer is just huge in the general society. And so, our patients are willing to say, "Look, I've got this difficult syndrome. I have a high risk of cancer." You know, I want to help be able to try to develop these newer types of technologies. So, it's really important.

Melanie Cole, MS: As complex as this is, and you doctors are  laying this out very clearly for us, Dr. MacFarland, in the pediatric population at the beginning and then as the teen becomes an adult, where in that spectrum does the discussion of fertility preservation and that transition to adult monitoring for this syndrome?

Suzanne MacFarland, MD: That's a great question and, I would like to hark back to something that Dr. Maxwell said about the advantage of having our combined programs that I can say, as a patient gets older, you are going to transition to Dr. Maxwell. She's right across the street And we will make sure that that transition is smooth. It has been such a huge part of ensuring that these patients follow up in adulthood.

But I would also say, as a pediatric provider, I work really closely with parents to start introducing that autonomy as early as possible. So even at time of diagnosis, we usually have a discussion of how should I talk to my child about this diagnosis. Parents do not want to scare their children very understandably about their cancer risk, but they also want their child to understand why they need so many extra check ins. And so, we have really careful discussions about developmentally appropriate ways to disseminate that information to a child and really fostering that honest dialogue between the parent and the child to make sure that the child feels comfortable asking questions about their own health, and that we're giving information in a way that's graded and careful.

So, we have, for example, a book that's  appropriate for very young children about what it's like to get ultrasounds and whole-body MRIs and to have Li-Fraumeni syndrome. As children get older, we  try to give that autonomy to a preteen and adolescent and to have those discussions early, for example, about breast health. As Dr. Maxwell said, we see late teen diagnoses of breast cancer. And so, we want them to understand that risk before they're making that transition to adulthood. Unlike other diagnoses where patients like to stay with us for as long as possible into their early 20s, we emphasize that they need to get their breast screening and need to start transitioning around 18 to see Dr. Maxwell. I think it really is a dialogue that starts with diagnosis very early and continues to ensure that the patient is empowered to take over their health at that transition point.

Kara Maxwell, MD: You know, I think that the fertility preservation question is such an interesting and timely discussion. And Dr. MacFarland, I'd love to know something we've never talked about. So, this is a great forum to say, do you guys start that discussion as kids? Because this has been such a changing field, right? One of the difficult things for these young women is sort of battling the knowledge of "Am I going to get pregnant? How is that going to affect my breast cancer risk? Do I want to have a prophylactic mastectomy before I get pregnant? Am I not going to breastfeed?" And now, add in your question, which is I might be facing a diagnosis where I'm on treatment that's going to prevent me from getting pregnant, the hormonal therapies for breast cancer, right? Going on tamoxifen, for example. And so, do I want to do fertility preservation, and when would I want to do that? Would I want to freeze eggs? Do I have a partner and we'd want to freeze embryos? And that is a conversation that was not a significant part of Oncology practice to be perfectly honest. And I am definitely having a lot more conversations with young patients about freezing eggs at this point.

The other part that comes into that discussion is prenatal genetic diagnosis and only implanting embryos that don't carry the p53 mutation when this individual eventually wants to get pregnant. And so, there's a lot of nuances there that come into that discussion. But I don't know from Dr. MacFarland's side, I know this is probably starting to hit you in the pediatric world as well.

Suzanne MacFarland, MD: Yeah, absolutely. And that it is something we bring up, when we go through new patient counseling, the risk of inheritance for an autosomal dominant condition. And in the pediatric world, when we're dealing with very young patients, we often will describe prenatal genetic diagnosis, but also say that it's not something we can necessarily counsel on for a young child knowing that technology may change over those years. But it is something that comes up. We have many patients come to us in the setting of their new cancer diagnosis. We do have a fertility preservation team here and we are involving them depending on what the therapy is going to be for that patient, whether or not they have Li-Fraumeni syndrome. But I think that Dr. Maxwell brings up the excellent point that this is going to come up earlier and earlier for patients, and we need to think ahead with them.

Melanie Cole, MS: You've laid it out and given us such great information doctors. I'd like to give you each a final thought here. Dr. Maxwell, you're both affiliated with the Li-Fraumeni syndrome TP53 Biobank at the Abramson Cancer Center. I'd like you to speak a little bit about the objectives of the biobank and the samples being collected from non-affected family members. Just give us a brief overview of that and what you would like the key takeaways to be for other providers.

Kara Maxwell, MD: I've heard so many times from my colleagues that, "Oh, there's no way that this person has Li-Fraumeni's syndrome, it's too rare," and that's something that's not necessarily true, and that there are one in 5,000 people with this syndrome which makes it rare, but not that uncommon.

Our team is focused, my research laboratory is focused on understanding how p53 drives breast cancer and other cancers. And so, that was the impetus for starting the biobank and we appreciate any referral from any of our providers to talk to the patients, not only clinically, but also their involvement in research.

And so, we consent basically. You know, I make the joke that anything that's coming out of your body, we want it. Obviously, their cancers that are coming out. From the blood, we're collecting immune cells to understand the relationship of the immune system with cancer development in patients with Li-Fraumeni. And then, in the lab, we are able to use these tissues to develop some novel models, and I think it's important to remember that the reason to study Li-Fraumeni syndrome is to help the patients with Li-Fraumeni syndrome, but it is also giving us insights into any p53-driven cancer. So, that's the goal of our studies. And we have been fortunate to open our biobank and be collecting from over 200 patients at this point.

Melanie Cole, MS: Dr. MacFarland, last word to you. Do you foresee a time when there will be effective treatments for Li-Fraumeni? And I'd like you to speak to other providers about your key takeaways.

Suzanne MacFarland, MD: Yes. So, I absolutely think that that is what we are all working towards in this research, as Dr. Maxwell said. I think that as we collect more samples and more clinical data, we're going to know more and more about the syndrome. And my hope is that someday there will be therapies to reduce cancer risk in these patients.

I think the shorter term goal is improving screening, and that's something that our research program is working diligently with other programs across the country to do specifically to develop protocols for incorporating things like liquid biopsy, which would be screening for cell-free DNA in these patients to detect cancer early as a method to improve our ability to detect cancers early. But absolutely, the hope is that someday we will be able to prevent cancer in these patients completely. And that's what we're all working towards.

Kara Maxwell, MD: Yeah. And if I could just jump on with what Dr. MacFarland said there is that this is an incredibly collaborative community. And we may have a Li-Fraumeni Syndrome Biobank that's in Penn and CHOP, but we are actively working with basically all the Li-Fraumeni researchers, as many as we can contact, right? And the community is so willing to work together. So, we're working with these larger consortiums, for example, called Lift Up and the Life Consortium. And it's amazing the way science is nowadays that these multidisciplinary, multi-institution, international groups can get together and put our samples together. And so, this is one of these efforts that really does take everyone to be involved.

Melanie Cole, MS: Thank you both so much for such an insightful conversation. And to refer your patient to Dr. Maxwell or Dr. MacFarland at Penn Medicine, please call our 24-7 provider-only line at 877-937-PENN or you can submit your referral via our secure online referral form by visiting our website at pennmedicine.org/referyourpatient. That concludes this episode from the specialists at Penn Medicine. I'm Melanie Cole. Thanks so much for joining us today.