Conversations with the Pioneers of Oncology: Dr. Larry Norton

Dr. Hayes interviews Dr. Norton.

Dr. Daniel F. Hayes is the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center. Dr. Hayes' research interests are in the field of experimental therapeutics and cancer biomarkers, especially in breast cancer. He has served as chair of the SWOG Breast Cancer Translational Medicine Committee, and he was an inaugural member and chaired the American Society of Clinical Oncology (ASCO) Tumor Marker Guidelines Committee. Dr. Hayes served on the ASCO Board of Directors, and served a 3 year term as President of ASCO from 2016-2018.

TRANSCRIPT

SPEAKER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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DANIEL F. HAYES: Welcome to JCO's Cancer Stories, the Art of Oncology, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insights into the world of cancer care. You can find all of the shows, including this one, at podcast.asco.org.

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Dr. Norton has stock and other ownership interest in Samus Therapeutics, Codagenix Inc, Martell Diagnostic, and Medaptive Health Inc. He's received honoraria from Context Therapeutics, Prime Oncology, the Sarah Lawrence Lecture, Context Advisory Board, Oncology Pioneer Science Lecture Series, Sermonix Pharmaceuticals, the Cold Spring Harbor advisory board, Codagenix, Agenus, and the Cold Spring Harbor external advisory board.

He has served as a consultant or provided advice to Context Therapeutics, Prime Oncology, the Context Advisory Board, Oncology Pioneer Science Lecture, Martell Diagnostic, Sermonix, Codagenix, Agenus, Medaptive Health, and the Cold Springs Harbor Laboratories. He has received expense reimbursement for travel and accommodations from the Oncology Pioneer Science Lecture Series, the BCRP Programmatic Review Meeting, the Breast Cancer Research Foundation, the American Association of Cancer Research, and Cold Spring Harbor Laboratory.

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Today my guest on the podcast is Dr. Larry Norton. Dr. Norton has been instrumental in so many facets of oncology it's hard to go through, but particularly, in breast cancer, and especially related to applying mathematical models of cancer kinetics that he developed with Richard Simon at the National Cancer Institute, and applying them really, to dose density strategies for chemotherapy and breast cancer, which we'll discuss. Dr. Norton was raised in suburban New York.

He received his undergraduate degree at Rochester University, his medical degree at the Columbia University College of Physicians and Scientists. And then he did his residency at Einstein Associated Hospitals in the Bronx. He then went on to complete a medical oncology fellowship at the National Cancer Institute from 1974 to 1976 and stayed there an extra year. And then he returned to New York and joined the faculty at Mount Sinai in 1977, where he stayed for about a decade.

He then moved to Memorial Sloan Kettering, where I think most of us think he was born and raised and lived his whole life. He's held many positions there. And particularly, he was responsible for really building the breast medical oncology service and starting the Evelyn Lauder Breast Center. He now sits in the Norman S Seraphim-- did I pronounce that correctly, Dr. Norton?

LARRY NORTON: Yes, you did.

DANIEL F. HAYES: Chair in Clinical Oncology, he's authored over 450 peer reviewed papers. He's won too many awards for me to list, as have most of my guests on this program. But in particular, he's won the triple crown, in my opinion. And that's the Karnofsky, the McGuire, and the Bonnadonna awards.

At least those of us in breast cancer would strive to win all three of those. And importantly to this series, he served as president of ASCO from 2001 to 2002, has served many roles at ASCO and has had a major footprint in where ASCO is today. Dr. Norton, welcome to our program.

LARRY NORTON: Great pleasure to be here. Thank you, Dan.

DANIEL F. HAYES: So we'll start with some of the origin stories. I know you weren't bit by a radioactive spider and got spidey powers. But I've known you for a long time.

And I know, really, your first love was music and that you started out to be a professional musician. Can you give us some background? What were your instruments? I know you went to Rochester specifically to be in music. And feel more than free to do some name dropping, because I think some of the people in music are people we'd all recognize.

LARRY NORTON: Well, I don't know whether that would be totally right. I've known a lot of people in music. My first love was music.

I grew up in Long Island, was able to commute in with one bus and one subway to Greenwich Village in the '60s, which was, really, the hotbed of much of what was going on in music to this day. I didn't even realize it was a golden age. I remember all the giants, Bob Dylan, when he was a very young kid in town, in small coffee houses.

But it was also in close proximity where a lot of the jazz scene was happening, and just to take the A Train would be very easy to get up into Harlem, where there's a lot of jazz things going on. Like a lot of kids growing up on Long Island, I had some musical education. I started off with the clarinet, went quickly into saxophone in terms of music. But I played a whole variety of instruments.

Like everybody else, I play guitar. I played percussion. I played bongos behind beat poets and was very excited to be really part of that scene.

I think one of the major turning points for me, actually, was the Vietnam War. Because like a lot of people of my generation, it did not seem to be reasonable war. And even McNamara wrote a book later saying, yep, sorry, it was a mistake. We were looking for things that could interest us and also help us serve our country in ways other than sacrificing our lives in Vietnam.

That's how medicine got into my life. It seemed to be the right compromise. Fortunately, starting off in Rochester which had the Eastman School of Music, which was a great influence on me, and a fantastic school, and has evolved continuously to be an even better school now.

It has a very active jazz program now, which didn't exist at that time. We had to do jazz on the sly, which was very easy to do, because there are a lot of jazz clubs in Rochester at that time. And it was really very easy to play jazz all night and then to play classical music all day. And that was totally, totally a great experience.

We were young. We didn't have to sleep at all. But I hankered to get back into New York. When the opportunity arose to go to medical school, I was fortunately chosen to go to Columbia, where I actually was able to play music and at the same time go to the medical school. But after a while, as all of us in medicine know, it becomes all consuming.

And so the medicine part of it just slipped. When it came to a lot of my friends from the old days up until the present day, very little performing, I've done a couple of benefits. I'll do the one namedrop with Elton John, because he's been so terrific at raising money for breast cancer research through the Breast Cancer Research Foundation. I had the great honor of being able to play with him twice--

DANIEL F. HAYES: How did you meet Elton John? I mean, it's not like you walk down the street and say, oh, hi, I'm Dan Hayes.

LARRY NORTON: Mutual friends, mutual friends in the arts, basically, one of our closest friends, close friend of his, close friend of mine, someone named Ingrid Sischy was a fantastic writer and editor, very involved with Andy Warhol in the beginning, and then continued a career in art criticism and art writing. And she was a friend of everybody and a close friend of Elton's and a close friend of mine. And so I think she made the original introduction. And he's really been terrific.

But the music is put aside, although I do play every day. I still keep that as a very important part of my zen escape from other stresses of life. Although, music itself has its own stresses.

The good thing about jazz is improvisation. So it's an immediate feeling, no such thing as a wrong note. You hit a wrong note, and you play around it. And it becomes a right note. And so music is still a very important part of my life.

DANIEL F. HAYES: That's terrific. Actually, I interviewed Hyman Muss a few weeks ago. And he and some others have introduced me to tying flies for fly fishing.

And it's sort of the same thing. I can take 15 minutes and tie a fly. I'm not sure it looks like anything official-like. But it's not medicine for a while, and that's good.

LARRY NORTON: Yeah, but medicine--

DANIEL F. HAYES: The other thing--

LARRY NORTON: I want to get back to this for a second, because I mean,

DANIEL F. HAYES: Yeah.

LARRY NORTON: It's not a separate thing. I mean, music and-- especially my early music education just taught me a lot that's really helped me in my career in medicine. I think it's very important for people to know. The talent for music is a talent to practice.

Essentially, anybody who can speak can-- has enough control of tones that they can actually do something with music. I'm not sure how much is really inborn ability. I'm not sure there is such a thing as a talent in that regard. But some people can practice for long hours successfully. And some people can't.

And I think that that's something that may be inborn. I don't know. I'll leave that to the developmental psychologists. But that is a very important trait, obviously, in medicine.

You have to spend a long time studying. You have to learn a lot. You have to concentrate a lot. You have to be able to concentrate on individual patients, when you're taking care of them. And that's been very important, but it's also empathy.

Music teaches you to feel what other people are feeling. You're not going to be a good musician unless you know how you're affecting your audience in a profound way. And you can sense when you're losing your audience, and you can change the direction you're going in. And when you hit something right, you can play it.

And that ability to feel what other people are feeling, I think, is really essential to be a good clinician. And music teaches you that. I think arts in general teach you that.

DANIEL F. HAYES: Actually, I hadn't thought about it. Do you think that your music and your mathematic leanings are tied together too?

LARRY NORTON: There is a tendency for mathematicians to be musicians, not true quite vice versa. Although they are-- good musicians really are mathematicians. But they don't know it.

A lot of people think math is the written equation, and it's not. It's a certain approach toward nature. Thinking in spatial ways, for me, thinking of shapes, and the way shapes form, the way shapes move over time and space, then you learn the tools for being able to write it down which is the actual mathematical notation.

DANIEL F. HAYES: Yeah.

LARRY NORTON: And the same thing with music, I mean, music isn't the notes on the page. I mean, that's a very poor reflection of what sounds you're making. It's the sounds. It's the sounds, and they go up and then down. That's spatial, and they go forward in time.

And so they're temporal, and they have meaning. It's not just random sounds. They have meaning. They connect to each other, and they tell a story, as we say in the jazz world. And the notes are a poor reflection of that.

Some of the best musicians I know can't read music. And as a matter of fact, it used to be said that if you want to be good jazz musician, you shouldn't learn to read. Because if you learn to read, you'll cheat. And you should be able to play by ear. And that's what's going to make you a better musician.

So I think math and music are very closely aligned. You have a problem to solve, when you think about it, and in novel ways that are not verbal. And the non-verbal way of thinking in music and in math are very similar, I think.

DANIEL F. HAYES: So let me segue onto how you changed paths. I know that it was-- I've heard you talk about it was a discussion with Dr. Ron Bloom, who I think has remained a good friend of yours, and then in association with Dr. Regelson at Roswell Park. Can you tell us about that?

LARRY NORTON: Well, Ron got me-- I mean, Ron, great, great oncologist, retired now, and his wife Diane also very, very important in the cancer world through her leadership of organizations. They both went to University of Rochester same time I did. I was actually perplexed at the end of one semester.

So both Ron and Diane were at the University of Rochester, the same I was. And I was perplexed at the end of one semester, because I had several opportunities to do things in the summer coming forward. One of which was very music oriented, and it was a very exciting possibility. But I was at that time considering a change in direction very strongly.

Math was one of the things that was drawing me. The question, should I become a professional statistician? That was the course that was turning me on mostly at that time. I thought physics was an incredible art form and was intrigued to that.

But I also had music that was drawing me. And also the question, of what could keep me helping people, and helping my nation, and keep me from necessarily bearing arms in Vietnam was a big concern. And I met Ron on the stairs of the Rush Rhees Library at the University of Rochester, a famous library, that by the way, has a famous ghost associated with it. That's a whole different story.

He said that he had this unbelievably wonderful experience the previous summer by working at Roswell Park Memorial Institute in Buffalo, New York State Cancer Research Institute, particularly under a guy named William Regelson who was just totally inspirational to him. And that was one of his major motivations to spend his career in cancer medicine, which I didn't even know it. I had another connection to Bill Regelson is that my father and his father actually knew each other. Because they were in businesses that touched.

His father ran a Catskills resort. And my father was a professional writer and travel editor at The New York Post. And so that there was that connection. So that when I relayed the story to my parents, they said, oh, we know Regelson.

So well, one thing led to another. And on a cold and rainy night, I took a bus into Buffalo, New York. And I met Bill Regelson in the laboratory at Roswell Park Memorial Institute.

It was late at night, and it was freezing rain, kind of miserable night. And he asked me a lot of very tough questions and was not very pleasant toward me. But the end of the interview, he says, I like the way you think. And I'd like to offer you an opportunity to work with me this summer.

And I jumped at that opportunity. And it was really, truly the turning point in my life in many ways. Because I, eventually, many years later ended up marrying Bill Regelson's daughter. My current wife--

DANIEL F. HAYES: I was not aware of that.

LARRY NORTON: Yeah. Rachel, the love of my life, it was an extraordinary experience, because I got very close to family. And she was in New York at Columbia, at Barnard, the same time that I was in medical school. And so that's how it all came about.

But anyway, Bill was really an inspirational character for many people of my generation who were in contact with him. Because he was just filled with enthusiasm, and energy, and optimism. You remember, the early days of oncology were very special. And by the way, if you want to catch a glimpse of that, it tends to be this book, The Death of Cancer. I'm giving it a big plug, fantastic book that captures the whole history of his life and cancer.

But the early days is very important for people to recognize what it was like in those early days. It was just an enormous challenge just to get people to pay attention. The possibility that drugs could actually be useful in the treatment of cancer, and it was often ridiculed. I can tell you a little story later about my early experiences when I came to New York in that regard.

DANIEL F. HAYES: So did you know you were going to be an oncologist when you went to med school? Or did that--

LARRY NORTON: I'll tell you two of the turning points in that regard that I think are particularly interesting. One is, at the very beginning of that summer, Bill Regelson brought me-- in those days, the labs were right next to the clinic, the inpatient service. And he brought me right from the lab a few steps in to see a patient who was admitted to the hospital with a pelvic tumor.

I don't know what type, didn't register in my mind at that time, but a pelvic tumor that had grown very large. And it actually had eroded out into the skin and was large, and infected, and bleeding, and just awful. And the patient was in terrible pain.

And he said, we're going to treat this patient with a new drug that I think is going to help her. And it's called methotrexate. And he treated with methotrexate, and I saw the I saw the medicine go into her arms.

And over the next few weeks, during that summer, I saw this tumor shrink down. I saw the skin heal over. I saw the pain go away. And it was, I'm seeing this monster eating this woman from the inside out. And I'm seeing just this yellow chemical going in there, and the monster being defeated.

It was like magic. It was something just beyond conception that, actually, you could take something that awful and that terrible, and actually give it medicine, and actually make it go away. And I said, this is a world I can't turn my back on. This is a world I have to be in.

This is just a magical, wonderful world, where you can actually heal things that couldn't be healed by other ways, I mean, totally beyond surgery, totally beyond radiation. And here's medicine going in. So that hooked me.

But at the very end of the summer, and toward the very end of my time there, another thing happened which would be a good segue. But also very important is the real person running medicine A at Roswell Park at that time was this person named Jim Holland. And Jim Holland was not there all summer, because he was riding a horse. And he had his daughter, one of his daughters on the horse.

And the horse was acting very, very jittery. And he was a little afraid of what the horse would do. So he went close to a fence, where he could actually unload the daughter, so she can grab on to the fence. And the horse didn't bolt and crushed his hip against the fence.

And so he was out with a fractured hip or pelvis the entire summer. But he was well enough toward the end of the summer to come in and speak to the summer students. And he came in, and he sat in a chair in the middle of the room. And all the summer students who gathered around him-- if I thought Bill Regelson had energy, to see this tornado of a personality in the room, with his loud booming voice and his probing questions, his clear intelligence and enthusiasm for his field and dedication to it was just inspirational.

And so it was a crescendo of a summer for me. And that was it. The experience of Bill Regelson, the experience of Jim Holland, I knew that I was stuck. And even though other things were attracting my attention, nothing was going to capture my life as much as the medical oncology.

DANIEL F. HAYES: You went on then to work with him for 10 years at Mount Sinai.

LARRY NORTON: Right.

DANIEL F. HAYES: In addition to what you've said, his obnoxious ties also always stood out for the rest of us. But those 10 years must have been unbelievable. Because the guy never quit thinking, at least in my experience with him.

LARRY NORTON: I mean, there's so much to say about Jim Holland. I had the honor to speak his funeral, the sadness to speak at his funeral, but it was the honor to speak at his funeral related some of the stories. But there's so much to talk about him that it's actually worth a whole book, even an opera, with the bigger than life personality he was.

But he captured something that I think was very important. And some of the early pioneers that we were talking about before really captured which is, I mean, these were real pioneers. I'll just give you a little side story. I mean, I came into grand rounds once, when I was working with him late, as I usually am to pretty much everything.

But nevertheless, I came in a few minutes late, and everybody was gathered around. And I remember it was a thoracic specialist, a pulmonologist, who was actually conducting grand rounds. And as I walked in the door, he says, how come you're late, Larry? Were you out there saving lives?

And everybody roared into uproarious laughter. Because medical oncology was the last step before the cemetery. Hopeless situations would all come to us. And then we'd give them drugs and not help people whatsoever.

And of course, I felt this deep humiliation. I was a young doctor at the time, and all these great, senior people, great luminaries were arrayed around. But that was the attitude of a lot of people in medicine at that time is that hopeless situations, send it to them, they'll take care of it. They'll hold hands, whatever.

And to see where we are today, and how many cases we cured, and how many patients we've cured, and how well we managed things, certainly, we don't cure enough. And you and I and our whole community is working hard on that. But we do cure a whole lot of people, and we do help their lives.

And we do keep them functioning for a longer period of time with the medicines. So the people that went into the field at that time and actually established the field of oncology, medical oncology, at that time were really had to have a real pioneering spirit. And so Tom Frei obviously pops to mind in that regard, and many others. I could give a long list--

DANIEL F. HAYES: Well, I should say, I had the great privilege of training with Tom Frei and the pleasure of interviewing Dr. Freireich who, sadly, passed away a few weeks ago. I did not get to interview Dr. Holland. But because of his friendship with Dr. Frei, Dr. Holland adopted me as well, even though I was never working with him directly.

And the three of those guys, I think our listeners need to understand, they were really cowboys. And they did things that we would now just, I think, repel, just have you can't do that sort of thing. But they did it, because they had to. As you said, there was nothing else to do. It took a special personality.

LARRY NORTON: Totally-- I mean, everything you're saying is-- I agree with. But also, that's why we are where we are today is because they took chances, because they had a vision, and they attacked that vision very, very aggressively. And I'll do one more namedrop in music that is one of my and still friend is Quincy Jones.

And Quincy Jones had this wonderful phrase in terms of jazz improvisation that was really very important to me. Sometimes, Larry, you have to jump without a parachute. And how do you get into an improvisation? You just start.

And then it has a life of its own. And the better you get, the more experience you get, the better you start it, and the better you're going to develop it. But you just got to start. Hit the first note, doesn't matter what it is.

And that kind of spirit of jumping in into it was really, very important. And I think that's something I really miss from modern oncology. If we're going to talk about where we are now compared to where we are then, a lot of things have changed that are very positive.

Obviously, the amount of science that we have to draw from now is just astronomically greater than what we had in the early days, when we're talking about very primitive things. The whole Norton-Simon thing was all about attacking cell division, the best way of attacking cell division. We're so far beyond that in so many ways. That's one of the bigger changes.

Our access to information, I mean, I had a question. I have to go to the library and got to cart catalogs, and pull books off the shelf, and open them up, and spend hours and spend days finding out one piece of information that now I can find out in about 15 seconds, if my fingers are slow on the keyboard, 15 seconds. And so that's it.

But one of the major things is that it was all about concepts then. It was all about principles. The principle that antimitotics could actually make tumors shrink and could be beneficial. That's a principle.

Combination chemotherapy is a principle. Dose dense sequential therapy, if you take it into further development of my area as a principle. And the overarching concepts on patient centrality of it also is that the early clinical trials were very small trials. Because each and every patient was a valuable piece of information.

They were almost collections of anecdotes. And obviously, we've evolved way past that in very positive ways. But what you learned from the individual patient was extremely important to that generation of pioneers rather than large numbers. And I think we moved away from that.

DANIEL F. HAYES: Actually, I'm going to interrupt you, because I think almost everybody I've interviewed has stories like you started out with. I saw a patient who I couldn't believe responded to X or Y. And I have the same stories.

And I'm hoping our young folks still believe that's as important as filling out the meaningful use things on their documentation. I told my own son, I want him to be a doctor and not a documenter. You need to document, but you need to be a doctor. Can I segue into--

LARRY NORTON: We ought to spend the whole podcast on that topic someday.

DANIEL F. HAYES: No, yeah, let's do that.

LARRY NORTON: Because the thing is-- well, because I think that the thing is, when you're taking care of a patient, and you're thinking, obviously, we're always thinking what's best for the patient, all of us. But you're also thinking of gathering information in a verbal way about the patient. So you can talk about that patient to your colleagues, or write it as case reports, a series of case reports is a different mindset than when you're thinking about how am I going to fill out my electronic health record?

And I think the mindset differences, and I frequently say to the younger people that I teach or that I'm in contact with, that they grew up in a digital world. And I grew up in an analog world. And the way you think in an analog world is very different than the way you think in a digital world. Maybe it's for the better. I mean, only history will tell, but I just miss that kind of analog thinking. Much of what we have today is because of it.

DANIEL F. HAYES: Let me take you into your role in modeling and especially with the so-called Norton-Simon hypothesis. How did you hook up with Richard Simon? And what did he teach you? Because I find him to be a fascinating person.

LARRY NORTON: Oh, a fascinating person, and obviously, one of the really important people in my professional career. The math was in there. Because along with, I mean, I studied math. I had studied math in college, and I was--

DANIEL F. HAYES: I should-- describe it. Just for a minute, describe what it is for our listeners.

LARRY NORTON: Oh, the Norton-Simon hypothesis and the--

DANIEL F. HAYES: Yes.

LARRY NORTON: All right. Oh, yeah, well--

DANIEL F. HAYES: Briefly, briefly.

LARRY NORTON: It's very simple is that way before my time, Skipper Schabel and colleagues at Southern Research Institute had described the way experimental tumors in their laboratory grew which was exponential. And they made the observation called the Log Kill hypothesis, which is the Log Kill rule which is a given dose of given drug kills a percentage of the cells that are present rather than an absolute number of cells, which is actually counterintuitive. It shouldn't be that way if you think about it in terms of biochemistry, but it is that way.

And we were all taught the Skipper Schabel model and Log Kill hypothesis. We were all taught that. And I was in the clinic taking care of a patient with Hodgkin's disease, nodular sclerosis Hodgkin's disease. And this patient had [INAUDIBLE] involvement with Hodgkin's disease.

Remember, I was working with Vincent Davita, a great influence on my life, Bruce Chabner, Bob Young, many people who-- George Canellos, who you know very well, great luminaries doing lymphoma therapy as a clinical associate at the National Cancer Institute. Hampton's patient is they had to Hodgkin's disease, got MOPP chemotherapy, roared into complete remission. Basically, two cycles of MOPP, was in complete remission. I've been involved in oncology since the early days of MOPP to show you how long I've been involved in oncology.

And I got four more cycles, because we give six cycles no matter what. We're two cycles beyond complete remission in that setting. And it was about a year. And the patient came back with mediastinal lymphadenopathy. The biopsy showed that was exactly the same lymphoma. Put him back on MOPP chemotherapy, and he responded again and went back into remission.

I don't recall whether it was complete remission or partial remission. And I said, this is really fascinating, because the math was already in my head at the time. Because I thought I want to graph it out and show how well it fit the Log Kill hypothesis. And it didn't fit at all.

I mean, it just didn't make any kind of sense. From a mathematical point of view, you couldn't make the equations fit. And about that same time, I became aware that others were describing that tumors were not really growing exponentially-- solid tumors were not growing exponentially as Skipper had shown in his laboratory models, a certain leukemia named leukemia 01210.

But rather, by a very strange curve called a Gompertz curve, which was developed in 1825 by Benjamin Gompertz to fit actuarial data, actually, not anything in terms of biology. And that's an S shaped curve. So it looks exponential at the beginning. And then it bends over and eventually seems to try to reach a plateau size.

And so I went back, and I applied the Skipper Schabel model mathematically to the Gompertz curve. And I realized that, for this individual patient, it would make a whole lot of sense if the tumor, when it was growing quickly, regressed more than when it was growing slowly at a very large size. In other words that the hypothesis is that the rate at which it would shrink is proportional to its rate of growth.

And since, in a Gompertz curve, the rate of growth is always changing, the rate of shrinkage changes as a function of time as a tumor shrinking down. And that was of germ the idea. And then the question is how to test it.

Under contract Arthur Bogden in Massachusetts did some animal modeling for us. And we published my first paper actually that showed tumors were growing in a Gompertzian fashion. And in fact, a subsequent paper showed that they regressed also in the Gompertzian fashion which is what the Norman-Simon hypothesis is.

Almost immediately thereafter, a couple of implications, in terms of cancer therapeutics, and I want to get back to that. Remind me to get back to that later on. Because this is around 1977 or so that all this was really becoming clear.

So it was actually one patient that made me think of it. I mean, frankly, it was one patient's experience that made me think of it. And that's what you were saying before, Dan, is the importance of learning from each individual patient.

DANIEL F. HAYES: And actually, it's gone on to be tested in many, many trials. But probably the most definitive was run by Marc Citron and CLGB under your guidance. And I just want to say a few words, because Marc passed away just a few weeks ago. He was really instrumental in ASCO and very, very generous to the foundation. We'll miss him greatly. But that trial of 97--

LARRY NORTON: 41.

DANIEL F. HAYES: 9741, demonstrated that dose density was superior to giving things in big doses for longer periods of time. Let me ask you about--

LARRY NORTON: I just want to second there what you're saying about Marc. I mean, just an incredible human being, an incredible person, incredible clinical scientist, and he was actually the first community clinician to chair a major national trial from a co-operative group which was just an intentional decision. I believe, you were involved in that decision, actually, Dan, Hyman Muss, certainly.

DANIEL F. HAYES: Marc and I started in a group at the same time. And we grew very close. I miss him. Let me ask you to look into your crystal ball for a minute and that is with precision medicine and targeted therapy. Does the Norton-Simon hypothesis still apply to that? Do you think chemotherapy still--

LARRY NORTON: Oh, yes. Oh, yeah, yeah. Well, first of all, I mean, I'm not-- now we're getting into sophisticated science topics here. But the thing is that I'm not, to this day, I'm not sure I have chemotherapy works.

I don't think that all of chemotherapy effect is just killing dividing cells. First of all, it's mathematically impossible. Does chemotherapy, does cytotoxic therapy affect the relation cell to its microenvironment? Does it affect its relationship to the immune system? These are all things that are under active investigation and active study at the present time.

There's more to what we do every day in terms of giving chemotherapy than just killing dividing cells. Chemotherapy can be very precise. I mean, methotrexate and dihydrofolate reductase, we talked about it before. It's very, very precise therapy, hormone therapy, tamoxifen and the estrogen receptor.

So we've been talking about precision medicine for a long time. It's just that our level of sophistication in terms of likely targets has changed. But still, it works. It's a law that fast things, things that grow faster regress more quickly than things growing more slowly how you return them. And I think that there are important lessons there that we still have to learn about cancer biology.

And that got me into some very exciting areas with [INAUDIBLE] and colleagues and to cell seeding theory with cancer, for example. And that story is evolving. And more data is becoming available there and much more sophisticated mathematics that will apply to those days that I hope I will have time to work on in the next few years to be able to actually establish those principles.

But I still think that we're doing something wrong if you're talking about a crystal ball which is that-- and it relates to what I just said before. We're so self-hypnotized into thinking that cancer is a disease of cell division. The vast bulk of our targeted therapeutics are oriented toward molecules that are related to mitosis.

You hear talk, that'll be a very specific talk about molecular pathways starting with genomics and [INAUDIBLE] signaling. At the end of the slide, it says, invasion, metastasis, and growth. It's a nice little package. And that's the answer. Well, I mean, that's a big cloudy area.

I mean, those are different things. Those are separate things. Those all have their separate biology. But they're all related. It is totally true.

And how are they related? And why are they related is one of the very important topics that we have to wrestle with, because that's what we really have to perturb. And I think that the, again, crystal ball guessing, or at least where I'm putting my energies now is we have all these incredible tools for developing medicinals that can attack molecules.

Are we attacking the right molecules by focusing in cell division? Should we be looking more toward perturbing tumor microenvironment relationships? Should we look at more sophisticated ways of using the immune system as one element in the tumor microenvironment, one of many in the tumor microenvironment, to accomplish the goals that we have to accomplish?

And are we actually looking at the right things in terms of molecular analysis in cancer by looking at pathways that are concerned with cell division primarily and secondarily with other things? Or should we be looking at molecular networks and molecular pathways in a more sophisticated fashion? Just like the early days of oncology, we have to be willing to take intellectual chances. And that's something I'm seeing much less of now than I did if you go back half a century.

DANIEL F. HAYES: We can go on with this one for a long time too. And we probably will the next time we get to sit and have a drink together when the pandemic goes away. I think it relates to dormancy. And I don't think we understand dormancy or how it is broken and how to treat it.

I have two things, and we're running out of time. One of those is you probably, in my opinion, have been the king of understanding the importance of philanthropy in our field, especially in relationship to what I see directly, which was your relationship with Evelyn Lauder and her husband, Leonard, of course, in the Breast Cancer Research Foundation. But I'd just like you to emphasize to the folks coming in the field how important that philanthropy is.

I think some of them believe it's dirty to get involved with that and ask people to give money. And you and other people I think have taught a lot of us that these folks want to help us. And it's important to address that in a dignified way.

LARRY NORTON: We're all in this together. I mean, I think that's the important thing to recognize as a physician or as a scientist. I said in a paper once that just as all of us are either actual or potential healers, all of us are actual or potential patients.

Cancer is a very important problem that needs to be solved. And people have to solve in every way they can, with our intellectual ability, our hard work in the clinic, our hard work in the laboratory. And people who are working hard in other fields who accumulate some element of wealth, or even people that just in normal life contribute small amounts, a lot of people doing small amounts adds up to a lot of money also. I mean, they're all part of the same process.

I mean, the importance of philanthropy is that-- and it goes back to what Evelyn said which I quote all the time. She was very instrumental in the building of our first breast center at Memorial Sloan Kettering and then our second breast center, which is freestanding building at Memorial Sloan Kettering. She and Leonard involved in every way and not just in terms of philanthropy, but actually thinking through the problems and helping solve them and design in every way.

When we built the first building that we had, we actually raised a little bit more money than we needed for the actual physical structure. So the question is, what to do with it? And obviously, a research fund at Memorial was established.

But then in terms of where else to go with it, she invited me over to her place in New York overlooking Central Park. And we sat in the kitchen, and we drank tea. And I said, what I perceive, and with my colleagues, I'm not the only one, obviously, who's perceiving this, is an explosion of science, basic science in understanding cancer, and an incredible collection of clinical investigators that can do clinical trials, and do large clinical trials as well as pilot clinical trials in our institutions. But I didn't see the connections being very tight. Because we were in different worlds, speaking somewhat different languages.

And we had to tighten those connections somehow and do something translating scientific advances in the laboratory into clinical benefit. It also allowed the scientists to understand what the clinical problems were and how to have the approach, and how we're going to do this. And she said, I've worked around creative people all my life in my professional life. And I know, you've got to identify the right people first of all.

So that's a little bit of a talent. But that the main thing is that when you identify them, you've got to give them freedom to use their imagination and the security to know that if they do something good and it doesn't work out, that they're not going to lose their job. Freedom and security is the secret of making progress in the field.

And I said, that's what we need. We need a foundation that can give the right people the freedom to use their imagination and the security to know that as long as they do good work, they're not going to lose their funding in a more traditional grant mechanism. And that's really where it started. So the whole thing is all based on that, is to get the right people and to give them freedom and security. And another part of it I just want to mention is networking to give people--

DANIEL F. HAYES: So let me focus this.

LARRY NORTON: OK.

DANIEL F. HAYES: Breast Cancer Research Foundation, how many people are you supporting? And how much money did you give this year? Just to give--

LARRY NORTON: Oh, about, oh, I mean, it's about 200 or so or more than that. Investigators, it's international at the present time. This year has been a tough year, and the next few years probably, because of COVID, because of the pandemic.

It's been a tough year. But in general, we've probably given away about a billion dollars. But it's not given away. It's actually an investment, investment in the future.

DANIEL F. HAYES: Yes. I agree.

LARRY NORTON: And it's all about bringing people together. New investigators come in, and they're used to gladiatorial combat when it comes to grant acquisition is that they have to fight against the people to beat them out. And what we reward is people working together and sharing ideas. And phenomenal things have occurred in that direction, phenomenal, huge programs in metastasis and molecular biology, Translational Breast Cancer Research Consortium which has been a fantastic thing that we've helped support. So it's really been a joy.

DANIEL F. HAYES: It's been great. Final 1 minute, the other thing you've done as well or better than most is mentoring. And I personally want to thank you for helping me in my career.

But probably, your greatest success is mentoring Cliff Hudis who's now the CEO of ASCO and is responsible for ASCO continuing to be probably the world's greatest oncology professional society. Actually not probably, in my opinion, for sure. So for that, I thank you.

We've run out of time, unfortunately. I think you and I could go on for another hour or so with this stuff which is what's fun about my getting to do this. But I want to thank you for all you've done for the field, for all you've done for so many of us in the field, and most importantly, for the patients who have benefited from what you've done.

It's pretty remarkable. This has been so much fun for me to get to interview so many of the pioneers. But you certainly rank up there at the top. So thank you very much for your time and look forward to talking to you later.

LARRY NORTON: Thank you so much for the kind words and for inviting me to do this with you, Dan. Thank you.

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DANIEL F. HAYES: Until next time, thank you for listening to this JCO's Cancer Stories, the Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories, the Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org.

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