When cancer strikes generation after generation in the same family, is it merely tragic coincidence or something written in our genes? In this powerful episode of the Read. Talk. Grow. podcast, host Dr. Denise Millstine welcomes Lawrence Ingrassia, author of the award-nominated A Fatal Inheritance, and Mayo Clinic oncologist Dr. Aadel Chaudhuri to explore Li-Fraumeni syndrome, a rare hereditary cancer condition caused by a mutation in the p53 gene. After losing his mother, both sisters, his brother, and nephew to various cancers, Ingrassia embarked on a journey to understand the genetic inheritance that shaped his family's fate. This conversation weaves together heartbreaking personal loss, groundbreaking scientific discovery, and hope for families living with inherited cancer risk. A must-listen episode about resilience, memory, and the power of living fully in the face of genetic uncertainty.
This episode was made possible by the generous support of Ken Stevens.
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Dr. Denise Millstine: Welcome to the “Read. Talk. Grow.” podcast, where we explore health topics through books. Our topic is hereditary cancer syndromes, particularly the one known as Li-Fraumeni syndrome. Our book is “A Fatal Inheritance: How a Family Misfortune Revealed a Deadly Medical Mystery” by Lawrence Ingrassia.
I'm your host, Dr. Denise Millstine. I'm an assistant professor of medicine at Mayo Clinic, where I practice women's health, internal medicine, and integrative medicine. My guests today are Lawrence Ingrassia, who is a former award-winning editor at the “New York Times,” “Wall Street Journal,” and the “Los Angeles Times.” The coverage he directed won five “Pulitzer Prizes” in addition to other prestigious awards. “A Fatal Inheritance,” his second book, was nominated for the “National Book Critics Circle Award” in Nonfiction and was named as a “Best Nonfiction Book of the Year” by Amazon, by “NPR” and “Kirkus.”
Larry, welcome to the show.
Lawrence Ingrassia: Thank you so much. It's a pleasure to be here.
Dr. Denise Millstine: Dr. Aadel Chaudhuri is a professor of radiation oncology and associate professor of immunology at Mayo Clinic in Rochester, Minnesota. He's a physician scientist at the forefront of translational cancer genomics and has been recognized as a distinguished clinician researcher. Aadel, welcome to the show.
Dr. Aadel Chaudhuri: Thank you. Thank you for having me.
Dr. Denise Millstine: “A Fatal Inheritance” is a combination medical memoir and exploration of the discovery of hereditary cancer syndromes through the lens of the author's own family experience that included several tragic losses of relatives to cancer at very young ages, woven together with a historical description of how researchers have come to understand cancer, including what drives it to occur more often in some people. Specifically, a variation in the p53 cancer suppressor gene that leads to a condition called Li-Fraumeni syndrome, which will be the focus of this “Read. Talk. Grow.” episode.
All right, let's jump into the book. Larry, as “A Fatal Inheritance” is part memoir, we know your inspiration, at least in part, your own family's history. Why did you finally decide to write this as a book?
Lawrence Ingrassia: Many families are touched by cancer, including, I'm sure, many of the listeners to our podcast. And I actually have a paragraph in the last chapter of the book, “When we are gone, we live on in memories. Those memories can remain surprisingly vivid for a long time through the people whose lives we have touched, however briefly. I was moved that so many people still treasured memories of my family members. But I know memories invariably can fade and even be lost when the people whose lives we touched are themselves gone. So while this is a book about scientific discovery begun by two tireless doctors, it is even more a love letter to my family, written to preserve memories for my children and their children and the children after them. Because I will be gone someday as well. And I don't want these memories to be gone with me. But a few seem especially cursed and mine was one of them.”
So my mother died in 1968. She was 42 years old. She had breast cancer and she'd had breast cancer, as best as I can remember, because I was a child from her 30s. Then. I had two younger sisters. The youngest died at 24, in the early 80s of abdominal cancer, and my other sister died at age 32, in 1987 of lung cancer. I had a nephew, one of my brother's sons had his first cancer at two. It was a rhabdomyosarcoma soft tissue cancer in his jaw, and my brother had his first cancer when he was 46. It was a lung cancer, a different kind of lung cancer than my sister. Now, my brother and his son both survived their initial cancers, but eventually succumbed. My nephew to his third cancer and my brother to his fifth or sixth cancer, depending on how you count it. And that was in 2019. And that's when I said, I want to know more about this condition that robbed me of my family. So I had no more siblings. All my siblings had died. My father died of unrelated heart condition.
So what I knew was about one sentence worth of what this condition was, that it was a inherited mutation in a gene called p53, as you mentioned, that normally prevents cancer. It works to fight cancer from developing, but when you have this inherited mutation, it loses a lot of its cancer fighting power, and it predisposes you to cancer.
And what was interesting about it, when I went online and said, okay, what is this? It was, it predisposes you to all kinds of cancers all over your body. This makes it different, probably from the best known inherited genetic mutation, which is BRCA, which is mostly breast cancer, and it also can be ovarian cancer.
So I was like, what is this? The first thing I found out when I googled is that it's quite rare. Probably not quite as rare it was as it was thought back then because more people are tested, but still very, very rare. And the other thing is that one of the two scientists whom it's named after is Dr. Fraumeni, along with Dr. Frederick Li.
Dr. Fraumeni was still alive. And I thought again, as you mentioned, I'm a journalist. I just want to know something about this. I wasn't really kind of intending initially to write a book, I just wanted to know more. And I did a telephone interview with him, and what he told me I thought, really intriguing.
Because he mentioned that back in the late 60s, about the time my mother died, that they had stumbled across a father and son who, a baby son, who had cancer, different kinds of cancers at the same time. They began studying this family and they found generations of different types of cancers. This family was riddled with cancer. And they published a paper speculating, could this be something familiar? And immediately they got a lot of skepticism. That's because at the time, cancer experts believed that most cancers were caused by viruses. So they were said, oh, it's probably, you know, kind of chance or maybe there was some environmental exposure. But they kept studying that.
The other thing that Dr. Fraumeni took more than 20 years of perseverance before they figured it out, that stuff came together and I said, now I really do think there's something interesting here. I want to find out more and that sent me on, it was a journey of discovery. I wanted to learn the science. I knew nothing about the science, had been a business journalist. I knew nothing about the science. I wanted to learn. I wanted to learn about this family. That was the focus of the research. My family wasn't the focus of any of the research, and I wanted to learn a little bit more about my family, why it took us so long to connect with the fact that maybe there was something hereditary going on in my family. It took more than two years of research to put all this together, and it resulted in this book, “A Fatal Inheritance.”
Dr. Denise Millstine: Well, and for listeners who haven't read the book, your background, Larry, as a journalist comes through because you keep the story moving. You make it so interesting. These are high tech scientific discoveries, scientific studies, and it reads in such a narrative way that it's just a pleasure to read it cover to cover.
So if anybody's feeling intimidated by some of the big words that Larry just said to us, please still be willing to go and read this book. Okay, Aadel, tell us your reaction to the book and also what it's like to work with families with inherited cancer syndromes.
Dr. Aadel Chaudhuri: I mean, I found Larry's book to be deeply compelling. I mean, a deeply compelling and human story that goes beyond, you know, what I'm used to in my in my clinical practice and my scientific research. I mean, I am deeply immersed in the science, and I'm deeply immersed on the clinical side. I've been doing this for a long time, and you could argue that, you know, I have everything I've done from my training, to my practice, you know, my medical school at Stanford to doing post-doctoral work and in labs from, you know, members of the National Academy of Medicine to doing it, you know, PhD with a Nobel Laureate.
I mean, kind of everything I've done has been to try to prepare me to try to do impactful research in the realm of genetics, genomics, in the realm of treating patients with the utmost excellence possible here at the Mayo Clinic.
But even you know what, reading Larry's book took me beyond all of that. I mean, it reminded me that there is more to this story that, you know, behind every patient encounter, behind every research question. There is a family, and there's a family that is wrestling with, you know, sometimes a fundamental question, why? Why me? Why us? Why my mother? Why my sister? Why my brother? Why my nephew? Why, why us? And Li-Fraumeni is unique in many ways.
You know, a lot of these cancer predisposition syndromes are unique. They're rare. And there's also the fundamental question, but why us? I mean, these families ask, why us? You know why. You know we, the Kilius family. Why we, the Ingrassia family? Why are we being affected? Why are being afflicted more than our friends and neighbors?
I mean, it's a fundamental question. And reading this book, it was a reminder that, you know, now we take it for granted. I mean, we have access to next generation sequencing. We have access to science here at Mayo. We have access to science, you know, here in the academic medical centers, to the point that many of the sciences now being rolled out to community health practices, to national health systems, you know, genomic testing, germ-line testing. Let's identify what's happening.
We didn't have that in the 70s. We didn't have that in the 80s. We didn't have that in the 90s. We didn't have that in the 2000s or even early 2010s. And so reading Larry's story reminded me that they were wondering why. And they really, despite having an investigative journalistic mindset, you know, as Larry had as his brother Paul had, I mean, there was no idea in the system.
There was really no clue until Joseph Fraumeni and Frederick Li and their colleagues, you know, David Malkin, until they developed the underlying science, until we turned that into a test, until we turned that into a way where we could answer the why. But for decades, we had no answer. And so, you know, it's really inspirational because as a physician scientist, that's the goal. The goal is to really take the science and translate it into practice and really to have a positive impact on the human stories, like the one we learned from Larry Ingrassia and his wonderful book, “A Fatal Inheritance.”
Lawrence Ingrassia: You know, Aadel, I love the way you describe it as inspiring because it is a heartbreaking story at times. And, you know, there were times when I teared up while I was doing my research, learning more about my sisters. I mean, I knew about it, but then you kind of really went to research and, you know, even more.
But it's also an inspiring story. And I try to tell people that. You're going to maybe shed some tears when you read this book, but also I think you're going to be inspired by that perseverance and by the dedication of the scientists working together all this time. And why? Because they wanted to solve this mystery, not just because it was a scientific puzzle. They wanted to help these families and to answer the question that you pose, which is why.
Dr. Aadel Chaudhuri: Thank you, I completely agree. I mean, this was, I think the way the science and the personal story was weaved together. You know, I've read several books and I'm well versed on the scientific literature, but I've never read a book that weaves that so perfectly. And I loved the, you know, how the chapters were relatively brief.
I enjoyed that. And I loved kind of the alternating the one chapter on the Kilius family. Another chapter goes right into Frederick Li and Joseph Fraumeni, you know in the lab, you know, doing their epidemiology. Or David Malkin, you know, doing sequencing, you know, doing at that point, southern blots. That was well before, express sequencing. I didn't even do a southern blot to try to identify what locus and p53 might be involved.
You know, I love the back and forth and I love for scientists and laypeople alike, just getting such a nice lay of the land, everything from the personal story to the deep science and everything in between weave together perfectly like a nice, beautiful rug.
Lawrence Ingrassia: I found you guys so interesting. I found the scientists so interesting just about the families and their motivations and just how they go about it. I mean, somebody mentioned to me, you know, that they were happy, the book captured how halting and slow scientific progress can be. It's not a straight line. You make mistakes along the way, you learn things along the way. And it's one scientist building on what another scientist had learned, which often leads to the breakthroughs. But you sound like breakthrough. It's like, oh my God, this just happened, kind of it started to happen. No, it takes a long time.
Dr. Aadel Chaudhuri: That's why we call it research. I mean, it's not just search, you search and then you get stuck in a corner, so then you research and indeed, if these things were easy, then, then it wouldn't be discovery. I mean, fundamentally, discovery is, scientific discovery is discovering something brand new and if it was easy, it would have already been discovered.
Dr. Denise Millstine: You both made mention that the Li-Fraumeni syndrome is rare. So it's not that it's particularly common, but there are many hereditary cancer syndromes. And I wonder if it would be helpful for our listeners to think about what makes a cancer more suspicious to be a part of one of these syndromes.
Larry, maybe talking about your mom would be a good place to start because she had far from what anybody would consider a typical breast cancer journey.
Lawrence Ingrassia: Yeah. But again, you kind of go back to the 1960s. And that was what I found one of the most interesting things about the research. She was young and young women in their 30s don't usually get breast cancer. Okay. But the state of research wasn't what it is today. Nobody knew exactly what had caused her cancer. And other interesting thing is, in our family, there was not a long history of cancers.
Okay? And typically in families with hereditary cancer syndromes, there is a long history. For example, if there's breast cancer in the family, you can also track it back for many generations. So one of the things that I learned in talking to Dr. Fraumeni when I explained this to him because of course we eventually found out that we did have the inherited p53 mutation, is that my mother probably didn't inherit it. She had what is called the de novo mutation when she was conceived. She was born with this mutation that had not existed in our family before. Both her parents, that her only sister lived into their 80s and never had cancer again.
So as a scientific expert, you know, kind of as Aadel will tell you, you can look at family histories and family histories often kind of can lead to clues. But there weren't any clues in my family before that. And the second thing that made it hard in our particular family to try to figure out what was going on, was that there were all different kinds of cancer. And indeed in family A, the Kilius family, which was the focus of a lot of the research of Li and Fraumeni, is that there were was a history going back many generations. I mean, that poor family, you know, kind of tragic, tragic history.
But again, there were all different kinds of cancers. Doctors didn't automatically say back then because so little was known about genetics. They didn't say, oh, there must be something going on here. They were thinking, you know, kind of maybe it's bad luck or we don't know what's going on.
It was this scientific describing and the advances in the understanding of genetics and the ability to look at particular genes and figure out what was the point of this gene and if it was, something went wrong with the gene, what might have happen. And that was something that took place in the 70s, 80s and 90s.
The medical mystery was finally solved in late 1990. Li and Fraumeni had been following this family and smartly had collected tissue samples of family members who had been dying of cancer for a long time. Also, they were collecting tissue samples from family members who did not have cancer. That was really important because when they finally developed the ability, as Aadel said, to look inside individual genes, what they found was the family members who had cancer had a mutation in this particular gene called p53, and the family members who did not have cancer did not have that mutation. There's a 50/50 chance of an inherited mutation. In fact, we learned later, I was the only one in my family who did not have the mutation. I tested negative for it.
It took all that time because they couldn't figure it out. And of course, I later learned out that that p53 was subsequently, has become known as the guardian of the genome. It is so important in regulating cell growth and regulating kind of keeping cells from going out of control, which is what cancer is. That it has been given this name.
I found it fascinating. But if you go back to the 60s, there was no reason looking at my mother, anybody would say, there is something going on here. Even in the 70s and 80s, before there was much of an understanding of genetics. It was still hard to say, especially with unrelated cancers. But it was with the 90s and starting with the discovery of specific genes like a colon cancer gene, Lynch Syndrome, BRCA, that doctors, when they saw these patterns, could say, I wonder if there is something hereditary here.
And oh, now we have the means to test it. Back then it was kind of difficult to test, but now it is actually very easy to test, as Aadel can say. You know, kind of he's lucky. I mean, but the advances we have a long way to go. There's no cure for hereditary cancer syndromes. But the advances in being able to identify and treat are remarkable. And that's the other thing that really, you know, kind of impressed me, you know, kind of over the arc of history, the understanding and advances in treatment have been remarkable.
Dr. Denise Millstine: Yeah. I love all that you've said about that. And I do want to delve into what p53 is. Aadel, I wonder if you'll also just comment on maybe the Kilius family, for example. So Larry tells the story of a young father being in the hospital with an acute myeloid leukemia, at the exact same time that his infant son, this is in the Kilius family, is diagnosed with a very unusual type of cancer called a rhabdomyosarcoma, and that it took researchers to have this light bulb moment to say, there's something unusual going on.
Can you just comment on those types of patterns? And, you know, it's not necessarily my grandmother had breast cancer when she was 80. So now I need to think about whether I have a genetic susceptibility. How do you help people see when there are these kinds of patterns that they might just want to at least delve into a bit?
Dr. Aadel Chaudhuri: It's an excellent point, Denise. You know, when I was reading the book, I was also like, wow, you know, can't you just see, like, I always want to go back in time and tell the doctors, like, you know, what are the chances, right? You have a young father with, you know, one type of cancer, and then the infant son has a completely different, completely rare form of cancer. Like, how can you not see that there's something genetic and hereditary happening here, right?
Yet the doctors just couldn't piece it together. Right. And similar, you know, in Larry's own family, I mean, the doctors just couldn't fit it together. And those initial families that Frederick Li and Joseph Fraumeni studied, I mean, they were up against so much resistance in the beginning, like, why are you even doing this?
And I want to take a step back and sometimes we take it for granted. I'm in the year 2025. I mean, very much so I want to just go back in time and almost like, you know, respectfully shake them and say, hey, like it's right in front of you. Like, don't you get it?
Sometimes in science we get we get a bit stubborn, with all due respect. I mean, you know, I'll give examples. I mean, for the longest, you know, for millennia, we thought the world, the earth was flat. For millennia, we thought that the solar system, the universe revolved around the Earth. There are there are countless examples, right? I don't want to digress, but there are countless examples. And I think what is relevant here is that, as Larry was mentioning for the longest time, science, biomedicine.
I mean, really our thought leaders, our Nobel laureates, our biomedical leaders were sure that viruses underpin cancer, like all cancer, right? That viruses underpin cancer. And then after that, they thought, okay, maybe there's some environmental component, maybe it's related to, you know, the factory that you know, that Larry's father worked in, for example. Right. That kind of what was happening in the environment. It was a fringe idea that genetics had anything to do with cancer. Right?
It took an awakening. It took, you know, renegades, as I'll use the word, with all due respect, like Frederick Li and Joseph Fraumeni to do that difficult epidemiologic work to get, you know, shouted down, you know, in conferences, but then to kind of get back up and continue the work and show more proof, right.
The talented physician from Nebraska being told by coastal elites that, hey, you know what you're doing. You know, maybe that maybe that works in Nebraska, but no in these and these conferences, it's all about viruses and secondarily, the environment.
It took that difficult work to then finally in the 80s and 90s and finally till today, that we have such a good understanding of genetics and the genetic underpinnings of cancer.
Viruses have a role they, you know, overall big picture speaking, lesser role compared to genetics. The environment, of course has a role. But genetics, especially these hereditary cancer predisposition syndromes, really are front and center. They have the foremost role in dictating these cancers that are striking at too early of an age with such a, you know, familial predisposition. Yet it took us so long because in many ways we were shining our flashlight in the wrong direction.
Dr. Denise Millstine:
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And it took a lot of people to come to the table, right, Larry? I mean, many of these discoveries wouldn't be, wouldn't have been possible without some of the mothers and grandmothers who were willing to tease back the family history, particularly in the example of the Kilius, correct?
Lawrence Ingrassia: It was really fascinating and I was very fortunate to be able to get access, thanks to the family permission, to the papers that were kept, that kind of enabled me to reconstruct the history of the research by Li and Fraumeni.
So after the father and baby son were discovered to have the cancer at the same time, Dr. Li and Fraumeni said, okay, we need to study this family. But remember, we're back in the 60s kind of collecting kind of records that are sprawling. There's not electronic records that you could get like an instant, you know, and there's sprawling and the other thing is like, who are these family members? We know who the immediate family members are, but, you know, kind of families get extended and kind of move across the country.
They have different last names. So how do we do this? Well, the mother, Irma Kilius, the mother of the young man who had cancer and of the infant son, the grandmother of the infant son who had cancer, she said, how can I help you, Dr. Li? And he said, can you help me track down the other family members?
And of course, you know, kind of she actually married into the family, but she was so determined, maybe something, maybe something kind of that I find can help my son and my grandson. And so she went about, she spent a lot of time tracking down family members, sending them notes. This person moved here. This person moved there. There were some in Ohio. There were some in Arizona. You know, kind of there were some in Nevada.
And so Dr. Li, you know, kind of had to kind of reach out to all of these hospitals, figure out, you know, kind of what had the person died of when the person died to build a family tree. And it was so critical, was so essential. Her help in aiding them build that family tree. Because, you know, by the time they published their paper in 1969, they had found this family in 67, the father, unfortunately, had died, you know, kind of quickly, the baby son actually survived until, you know, in his late 20s, a little bit like my nephew had multiple cancers before, you know, kind of one finally killed him.
But it took, you know, kind of all that time for them to gather this information. And by 69, when they published a paper, they had basically a family tree of six generations knowing who had what cancer, when, when they died and why. And that was what enabled them to say, you know, we don't know what's going on here, but this is an unusually high number of cancers in one family and across generations of one family. And this makes us wonder if there might be something familial, even though we can't say for sure.
As they had some answers to the people who were the skeptics. For example, skeptics says, well, it's environmental. And they said, well, you know, if it's environmental, that might be possible. If everybody this all these family members were like living in the same city, next to the same factory, spewing the same kind of carcinogens. But this is a sprawling family. By this time they're living many different parts of the country. So that seems unlikely to us.
And I think that's part of the scientific disquisition that, you know, how they scientists go about, you know, kind of looking at all the evidence, but also kind of raising questions, too, and not just accepting the simple answers. That's what took them, I think, to eventually solve it.
Dr. Denise Millstine: Well and part of the brilliance is that these were all very unusual cancers. It would be one thing if it was a family tree of all breast cancer, for example. Then you could see this clearly tied together, but they were able to recognize like these are either typical cancers happening atypically, like in a younger person or more aggressively, or they were truly rare types of cancers.
Okay, Aadel, I know our listeners want to hear so what is p53? What does it mean to have a mutation? What is the crux of the matter here with Li-Fraumeni syndrome?
Dr. Aadel Chaudhuri: Absolutely. I mean so p53, as Larry was mentioning, we refer to it as the guardian of the genome. I mean, it is a tumor suppressor gene, is a fundamental tumor suppressor gene that will ultimately prevent cancer, when functioning well. And the way that it does that is that when a cell starts dividing, if too rapidly, gets mutations, starts dividing too rapidly, p53 will say, okay let's slow down, let's halt, and actually, there may be a problem. We're going to let this cell die, rather than it turning into cancer. So it's really a guardian of the genome. And it's willing to sacrifice the cell for the greater good.
Now when p53 itself gets mutated, you have that, that checkpoint gets lost and that cell can start dividing and dividing and dividing and accruing more and more mutations and kind of spinning out of control. And you don't have that guardian there, that checkpoint there. You don't have that, you know, let's pause for a second and let's assess before we divide again. You don't have that anymore. And all of a sudden you spin forward towards cancer. Now genomics is complex. The genome is complex. You know we are complex. It's you know of course not as simple as that.
Even in families with Li-Fraumeni syndrome, where you have a mutated version of p53, you have another version that is able to step up in its place until it gets mutated spontaneously. And that can happen in varying times in one's life and in different tissues in one's body. So that's why, for example, and you know, Larry's brother Paul developed his first cancer much, much later in his life, in his 40s compared to his sisters who developed cancer in their 20s and 30s, or his nephew, who developed cancer at the young age of two.
So that remaining p53 can stay intact for a while and it depends on where in the body it can develop a spontaneous mutation. And you do have other tumor suppressor genes as well that function, that have some redundancy. You have a number of oncogenes, you have a number of tumor suppressors, and you have complexity in the system.
But overall p53 is critical. And as a result Li-Fraumeni syndrome is unique in the sense that you have a proliferation of potentially many different cancers that can affect many different parts of the body within the same family really related to the germline mutation of one gene.
Lawrence Ingrassia: I just had that excellent explanation. Kind of it's so difficult to do kind of boil down, but.
Dr. Denise Millstine: I feel like maybe he said that before. I feel like he has practiced that, which is why I pitched that question to him. But I do have a question for you, because you were quite bold at the beginning of this. You said, I knew very little about this when I started my research, and I wonder if you'll share somewhat with our listeners, not just about the p53 mutation that's related with Li-Fraumeni, but how much impact it has in other roles in cancer as well, in terms of treatment strategies and things that you then discovered through the process of writing the book?
Lawrence Ingrassia: Well, I think the one thing I want to note is how we finally found out that we, you know, kind of there might be a mutation. In 2014, again, this is quite a number of years after the discovery of the p53 mutation and Li-Fraumeni symptom. One of my brothers doctors say, hey, you know, I think that you might get a genetics test.
I'm surprised that it wasn't suggested earlier, but I think part of the reason getting to your question is with there was a lot of uncertainty about what to do about that.
So if you know you have a mutation, there's not necessarily a lot that you can do. Certainly back then, remember this is a cancer suppressor gene that protects against cancer throughout the body, which means that you can get cancer anywhere. And so that means which is different than say, BRCA, which is primarily breast cancer. Now there is a treatment if you have the BRCA mutation okay. And that is you can have a double mastectomy. I mean it's not a great option and you can do other things too.
But that but if you think of p53, there's not you can't start lopping off all parts of your body. So it is fundamentally different, I think, in that way. And so I think his doctors were right in saying that there's not a lot that can be done. So my brother got tested and sure enough, he tested positive. And he said, you know what, I'm actually relieved in many ways because now we know, getting back to our discussion at the beginning is, you know, kind of the answer to why. Now we know why.
I got tested about a year later and tested negative, which I had kind of assumed because I was in my 60s, had never had any cancer. If you have the inherited p53 mutation, there is a 95% chance of getting cancer in your lifetime. I mean, it's staggering. In fact, by age 40, there's a 50% chance of getting cancer and often multiple cancers if you survive your first cancer. And that's versus 5% of the overall population.
So what to do? Again, you know, I think there's hope that maybe someday we're going to find ways to fix inherited mutations, kind of using the CRISPR editing technology that has been discovered. But for now, you really have to try to find the cancers early. And so one of the things that Dr. David Malkin, who was we've mentioned, who helped find the p53 mutation as a postdoctoral student back in the early 90s. He was confronted with this as he kind of continued doing his research and was also practicing trying to help families like this.
And he said if we did rigorous annual screening, would it increase the survival rates of families with the p53 mutation, inherited mutation? So over a five, six, seven-year period of time he studied these families, gave, gave, did rigorous screening. So you would go in and get, you know, kind of a full body MRIs, you would get blood tests. With the goal of if we do this often enough because we know these people are highly like to get cancer, if we do it often enough, we can detect cancer at the earliest stages. And that's the best way to defeat cancer, is to catch it at the earliest stages.
And combined with the fact that you have a lot more targeted technologies, targeted medicines that have been developed over the past 10 to 20 years in particular, those two things I think have made it. It is as my book says, for many people, a fatal inheritance, but your chances of finding it are much better. Thanks to all the early screening and thanks to the improved therapies that doctors have in their arsenal to fight cancer.
Dr. Aadel Chaudhuri: Yeah, I mean, it's such a great point. I just I just wanted to add, Larry, I learned so much, you know, reading your book and I actually I learned about some of the history behind some of the things in our medical practice that I take for granted.
And one of those was the story behind annual MRI screening and how David Malkin, you know, how he came up with it, the story behind that, and ultimately how that went into fruition. I mean, this was a very new idea. You could argue, honestly, a controversial idea when David Malkin first came up with it, he was confronted with really this almost anxiety inside this almost inner conflict inside that. Okay, I now have I discovered the genetic underpinning of Li-Fraumeni syndrome, but there's nothing that we can do about it.
And as a clinician scientist, I mean, sometimes he made the scientific discovery when he was a postdoctoral student, postdoctoral researcher at Harvard. Now he's practicing independently at Toronto, and he's wondering, okay, how do I build upon what I've done to really make a difference? And he pitched this as I as I learned from your book, he pitch this to Frederick Li, you know, really asking for his blessing that, hey, I know doing whole body MRI and all of the infrastructure that that requires and you know, we're going to do this annually from, you know, from the time that these people are basically born, you know, from a young age, they, you know, their p53 mutations identified from that point on, annual whole body MRI and deep clinical exam, you know, does this sound feasible? And Frederick Li basically gave a blessing and said, yeah, go go for it.
And then essentially he just went for it as a physician scientist, he that okay, I'm going to do it. And he went for it. And boy has that been great. With patients with Li-Fraumeni syndrome, with this protocol, cancers are being found earlier, as he showed with the Toronto Protocol. You can treat them earlier and then ultimately extend life.
And I would argue that this has opened up this entire arena of early cancer detection and interception, which is a thriving arena now. It's something that, you know, one can open up “The New Yorker” or “The New York Times” or the “Wall Street Journal” and read about these early detection assays and this concept of early detection and interception.
Can we detect cancer early? Can we treat it? Can we cure it earlier? And can we make cancer less deadly? And a lot of that, I would say, kind of goes back to how physician scientists take in initial discovery with the real deep yearning to turn that into a meaningful difference for his patients.
Lawrence Ingrassia: Yes, it's not just the science for science’s sake. It is to help the patients. And that, again, was something that just touched me when I was writing the book, is how much these physicians cared.
Dr. Aadel Chaudhuri: Indeed, I loved it.
Dr. Denise Millstine: I wonder if you'd comment as well about what has changed with the testing. So when we think about the p53 mutation being discovered 35 years ago, that's really not that long ago. But you made a quick mention of how the testing wasn't even as available essentially ten years ago.
Lawrence Ingrassia: Oh, so I'll tell you kind of what, when I got that when I got tested ten years ago. It was nine years ago. It was it was 2016. It would have cost me several thousand, $3 to $5000 to get tested.
My brother asked his doctors, can you find a study that he might participate in that will be able to get tested for free and we found that. Lucky me. And that's where, you know, kind of I tested negative, which was great because that meant I couldn't pass it on to my children. I have two children, and even though it's a 95% chance of getting cancer, if you had it in a lifetime, if you have p53, there's 5%. Nobody knows exactly why they're 5% who don't get cancer. So I could have been one of those. So that was a great relief to me and my family.
Flash forward today. Going back to the 90s, you could test the one gene at a time, one mutation at a time. By 2016 you could get a what is called the multi-panel test, which could test for 20, 30, 40 different of the most common cancer mutations or other types of genetic mutations that cause health issues.
Today you can get those multi panel tests, which I'm sure are more accurate than they were nine years ago, cost about $250. So the great advantage now is and that's one of the reasons I think we're actually finding that that even though these inherited mutations are rare, they're not quite as rare because more people get tested, because it's a lot more.
And the advantage of being tested is once you know that you're positive, as Aadel mentioned, is then you can, should I get screened and you can catch the cancers earlier. So even though we do not have a cure yet, the advantages of knowing, I think we have to acknowledge here, for some people, it's scary to know that you have a genetic mutation in your family that you can pass on to your children.
Some people actually don't want to get tested because they would just like to kind of, hey, I'll take my chances, or it's just too painful to know that. I would say that knowledge is power. Not knowing doesn’t mean that you don't have it? I would rather know. So then I know what kind of screening we ought to do, how frequently, and so we can catch the cancers early, because otherwise you're just kind of waiting for chance. And it is scary. But I think it's really important, and I'm sure that you must deal with this in dealing with families from time to time as well.
Dr. Aadel Chaudhuri: Absolutely. I mean, it's incredible what we can do now with modern genomics that we can test for multiple genes, multiple mutations across several different large panels of genes with next generation sequencing in ways that, you know, we just couldn't in the 90s or more 2000s. And that's powerful. Now we're at a point where it's almost a question of who do we deploy this in?
And, you know, where should we really get insurance coverage? I think, you know, what I'm seeing in clinical practice is oftentimes we are not doing the germ-line testing until a patient has cancer. So okay, a patient comes in with cancer. Then we're doing next generation sequencing on their tumor as well as on their germ-line to see okay what inherited mutations might there be. And if there is something deleterious found then will extend that out to the family members.
Or another situation I'm seeing it in is, you know, when a couple decides that they want to have a child or at the time of pregnancy confirmation in the OB office, then that test is offered to both the mother and the father to see what germ-line predisposition might you have and what is the chance of passing that on to the baby.
Dr. Denise Millstine: Will you just pause there a second and just distinguish what you just said about the genetic testing of the cancer itself, the tumor itself, and what you mean by germ-line testing, how do those differ?
Dr. Aadel Chaudhuri: So tumor testing means that you have a tumor that is biopsied or resected, and you're doing sequencing of that tumor, and you expect that tumor to have a number of mutations. I mean, it is already cancer. We know it's apparent, but we want to know what mutations it has so that we can potentially target some of those specific mutations in order to kill it. Certain cancers have certain Achilles heel mutations that are druggable, and if they have those, we want to know about it so that we can drug those mutations and potentially kill it.
Dr. Denise Millstine: We'll call that targeted therapies very often.
Dr. Aadel Chaudhuri: Targeted therapies and this is especially important in the metastatic setting. In the non-metastatic setting, we’ll often just try to remove it or deal with it with local therapies. But in the metastatic setting we especially want to know are there mutations that we can drug to really keep the cancer from growing and taking over and really, you know, causing an issue in terms of survival in terms of morbidity and mortality, right. That is our goal, kind of broadly speaking.
Germ-line. When I say germ-line testing, I'm really saying can we do a test on normal tissue, right. Whether it be blood or skin tissue or a buckle swab on a patient, cheek swab? Can we do a test of normal stuff from the individual to see? Is there some sort of hereditary predisposition that was inherited? Is there something like a p53 mutation that was inherited and if that's the case, then that patient may not have a cancer then. But they have a predisposition for that cancer that they could have passed on to their family members as well.
Dr. Denise Millstine: And that's in all your cells. It's not in your cancer cells only that's in all your cells. And that's a distinction that making.
Dr. Aadel Chaudhuri: Exactly. And so, you know, many times in our standard practice, even at specialized places like, like here at the Mayo Clinic, we reserve the germ-line testing, the testing of the normal cells for when a patient is actually coming in with a diagnosed cancer. We're like, okay, you have cancer. Were you predisposed for it? And we'll do that germ-line testing of their normal cells at that time. And if that's positive, then we'll extend it out to their family members.
And it's an open to discussion. Should we do this on a broader setting? How a more population level setting? I'm seeing that happening when couples come in for pregnancy counseling, or they're coming in with a positive pregnancy that that is offered at that time to see what is the risk of having a cancer predisposition syndrome. And if you have it, what is the risk of passing it on to the unborn child? But it's an open discussion.
Should we be broadening this even further, or are there certain risk categories where we should be testing this a little bit more briskly. In your last chapter, I found it so moving when when you celebrated, you know, living a day longer than you know than than any of your family members. And that was I found that incredibly moving in how you decided that you were going to go take a flight, that you were going to take a flight in a single person plane.
Lawrence Ingrassia: Yes.
Dr. Aadel Chaudhuri: You were up in the sky. And I wanted to ask you, and you wrote about it so beautifully, but I wanted to ask you, given I have this opportunity to speak with the author. Well, what was going on in your mind as you were taking off and as you were in the air?
Lawrence Ingrassia: Again, you know, I think I partly I did it for me, but I really did it as much for my family members because they couldn't, you know, I think of my sisters died so young, 24 and 32 when my mother, who died at 42, my nephew died at 39. These are times when we have our full lives ahead of us.
And yet what were they robbed? What experiences were they robbed of. And so I thought a lot about I wanted to do something special on that day. It was the day that I became the longest living member of my family, a bit over 69, because my brother had died at 69. I wanted it to be something a little bit out of the ordinary. And so I got into this, you know, I thought about, well, do I want to go hiking in Redwood Forest? What do I want to do? And I decided in the end I wanted to do something really kind of unusual a gyrocopter. It's like getting into a motorcycle fly motorcycle. It's that small. Wow. And. And the whole time I just was thinking, this world is breathtaking.
Dr. Aadel Chaudhuri: Wow.
Lawrence Ingrassia: This experience is breathtaking. And I need to kind of try to embrace and live these experiences because they can't. And their lives were shortened and mine wasn't. And that's what it was about.
Dr. Denise Millstine: That's so beautiful.
Dr. Aadel Chaudhuri: Thank you so much for sharing. I mean, I read that I mean, it was it's powerful in the written form, but I had it on my to do list to ask you, and I'm glad I did.
Lawrence Ingrassia: Well, thanks for all the work that you do on behalf of these patients. I know that dealing with families like this who are always, you know, kind of asking the why and the pain, they're incredible families, but there's a lot of suffering.
Dr. Aadel Chaudhuri: Thank you, Larry. And honestly, reading your book, you know, supplemented my why I mean, it did, you know, it gave me another injection of inspiration and so I appreciate you and I appreciate all the work that you've done. And just know that, I mean, your work truly resonated with me.
Lawrence Ingrassia: Thanks again. Hey, this has been really I've done a lot of these. This is easily one of the best. I could tell that you really, really kind of took time to read the book and understand the book and I'm deeply appreciative of them.
Dr. Denise Millstine: As are we of you. Thank you both so much. This has been such a fascinating conversation, and it is mind blowing all that we've been able to tackle. And I promise our listeners who haven't read “A Fatal Inheritance” yet that Larry makes this very story driven and narrative and brings it to the human side. It's an engaging book from which even a distinguished clinician researcher has learned a great deal, as have I.
I want to thank you both for being here for this incredible conversation. I want to encourage listeners to go out and read “A Fatal Inheritance” by Larry Ingrassia. Thank you both.
Lawrence Ingrassia: It was really my pleasure. It was a wonderful conversation.
Dr. Aadel Chaudhuri: Absolutely. My pleasure. I mean, congratulations on an excellent book that is highly compelling that I got so much out of and that, you know, I know any reader would get a lot out of. Thank you, Larry, and thank you for sharing the story of your family.
Dr. Denise Millstine: “Read. Talk. Grow.” is a product of the Women's Health Center at Mayo Clinic. This episode was made possible by the generous support of Ken Stevens. Our producer is Lisa Speckhard Pasque and our recording engineer is Rick Andresen.
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