Conversations with the Pioneers of Oncology: Dr. Marc Lippman

Cancer Stories: The Art of Oncology

Dr. Hayes interviews Dr. Lippman discuss on being one of the first translational scientists in solid tumors.

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.

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.

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 insight into the role of cancer care. You can find all of these shows, including this one, at podcast.asco.org.

Welcome to Cancer Stories. I'm Dr. Daniel Hayes. I'm a medical oncologist and a translational researcher at the University of Michigan Rogel Cancer Center. I'm also the past president of ASCO.

I'm really privileged to be your host for a series of podcast interviews with the founders of our field. In this series of podcasts, I'm hoping I'll bring appreciation of the courage, the vision, and the scientific background among the leaders who founded our field of cancer clinical care over the last 70 years. I think that by understanding the background of how we got to what we now consider normal in oncology, we can work together towards a better future for our patients and their families during and after cancer treatment.

Today, I am privileged to have as my guest on this podcast Dr. Marc Lippman. Dr. Lippman was really instrumental in the early studies of the role of the S receptor in breast cancer. And personally, I consider him with his former colleague Dr. William McGuire the first investigators to perform what we now call, quote, "translational," end of quote, science in solid tumors.

Dr. Lippman was raised in Brooklyn. He received his undergraduate degree at Cornell where, by the way, he played on the varsity tennis team. And then he got his medical degree at Yale. He did his residency at Johns Hopkins and returned to Yale for a fellowship in endocrinology.

Somewhat surprisingly, to me at least, he served a year from 1970 to '71 as a clinical associate in the leukemia service at the National Cancer Institute while simultaneously working in the laboratory of biochemistry with Brad Thompson, with whom he published extensively. Dr. Lippman has authored nearly 500 peer-reviewed papers. He co-edits Diseases of the Breast, which is considered the Bible of breast cancer with Dr. Jay Harris and Monica Morrow and Kent Osborne. And fundamentally, he has mentored the leaders of breast cancer in the world, in my opinion. Welcome to our program.

Hello.

I have a number of questions I'd like to ask you. First of all, clearly, you took a really unusual path to being a cancer doctor. To my knowledge, you actually never formally trained in oncology. Can you tell our audience how you went from being an endocrinology Fellow to being an oncologist?

I think it's worth it, from my vantage point, to give a little background about me. I came from very, very intellectually rich family. And there was never any question that I was going to do some kind of science. I was certain that that's where I was headed.

And when I was in medical school, I think it's important that while everybody was doing research at the school like Yale, a lot of medicine as we now think of it as evidence-based was completely mysterious. In those days, when I was starting medical school, really, I think the only fully scientific field was infectious disease because we had Cox postulates. And we knew what drugs killed what bugs. And we knew what bugs caused what diseases, for the most part. And that was wonderful.

But endocrinology, at that time, was completely functional assays. It was completely not scientific. You looked to see if the rabbit ovulated or something like that for a bio assays. And Nobel Prize winning research was done, which developed the radio immuno and the radio receptor assay. And that completely transformed endocrinology over night.

And within about one year, virtually every endocrine disease, the pathophysiology of Addison's, thyroid disease, you name it was worked out based on being able to measure minuscule amounts of hormones. And to me, this was fabulous. I was going to be an endocrinologist. I had no doubt about it. This was real science. And I could get into it.

When I was in medical school, you had to do a thesis. And for reasons that I'm not even sure of now, I can recall, I got involved with a guy who was a hematologist. But he did work on leukemia. And I enjoyed that work greatly. It was very interesting.

And right about then, you may recall, there was a minor episode going on called Vietnam. And many physicians or people who were about to become physicians, myself included, weren't very anxious to go to Vietnam. And one of the main alternative routes was to become an officer in the public health service at the NIH and to do your military service at the NIH. And that seemed like exactly what I wanted to do.

It was a very unusual process. People at the NIH picked you for their own personal lab. And because I had been working in this hematology lab, a scientist, an administrator actually at the NCI invited me to join his lab, Saul Perry. And I took him up on that because that seemed like my only alternative.

But after I finished my internship and residency and showed up at the NIH, because I was part of Saul Perry's group which was the leukemia service, I had to spend a year on the wards taking care of extremely sick people, most of whom died during that year. But because of my love of endocrinology, I kept studying all kinds of stuff around endocrinology, took the molecular endocrinology courses. And then I met this wonderful mentor, Brad Thompson.

And my first project with him actually was an attempt to combine leukemia and endocrinology. And I started measuring glucocorticoid receptors in leukemia. And that's, frankly, some of the best work I ever did. We showed that they existed, that they were receptors, and that they predicted response. I mean, we did in leukemia what people were doing in breast cancer, and I thought that was pretty interesting. And there was always this tension in my mind between the science of endocrinology and the almost complete lack thereof, at that time, in oncology.

And I thought that I might try to think about putting them together. But I needed to do formal endocrine training. So after I finished my clinical year at the NIH and my two years in the laboratory with Brad Thompson, I went back to Yale to do endocrinology. And I thought that's where I would complete my career.

After I'd been there about a year, Paul Carbone called me up and said, would I like to come back to the NCI and join the breast cancer service? And I have to tell you candidly, I had never treated a case in breast cancer in my life when I went to join the breast cancer program at the NCI. And I completely learned everything I learned about breast cancer absolutely on the fly.

So what made Dr. Carbone call you to do breast cancer?

Well, I'm not absolutely certain. I had done well at the NCI. I'd been very interested in a lot of things. And I'm not certain I can remember anymore. I don't remember why Paul called me, but he did.

And at that time, I had been looking at several endocrine jobs at a variety of institutions, including University of Chicago. And I was thinking I'd just spend my life as an endocrinologist. But I thought this was such a great opportunity to pursue my research that I decided to take my chances.

I was extremely full of myself in those days. And I didn't see the problem that I had never treated breast cancer. I know it sounds dumb to say it. But I actually said, well, OK, I'll figure this out. How hard can it be? And I guess I didn't find it all that hard.

And at that time, because I had already gotten into what I would refer to as molecular endocrinology, half of which was steroid-hormone action, I was highly familiar with the work of Elwood Jensen, who was the real pioneer at that time, one of two actually. So naturally, it made sense to me to take the work I'd already done in glucocorticoid receptors and try to make models in tissue culture for how breast cancer responded to hormones, the kind of thing you would never suggest that a newly minted faculty member try a completely insane project, which I was extremely fortunate that it succeeded.

You refer to Elwood Jensen. Tell us more about Dr. Jensen and what he did that got you where you were.

Well, Elwood was a tremendous scientist and basically a chemist. And people don't understand how technology sometimes makes a field possible. And just as I mentioned before, radio immuno and radio receptor assay made the entire field of endocrinology and now so many other subspecialties of medicine possible as you measure pulmonary and GI and cardiac hormones, in the same exact sense, what Elwood succeeded in making was radiolabeled steroids. And you can't do receptor assays unless you have high specific activity compounds.

We don't use radio isotopes touch so much anymore, and people don't appreciate that. But there was absolutely no way to measure the binding in picomolar and centimolar ranges without high specific activity steroids. And Elwood was able to manufacture created hexestrol, which is a similar compound to estradiol. And with that, he was able to basically separate bounds from free hormone and prove the existence of receptors. It was extremely important studies that he did at the time. And it opened up the entire field of hormone dependency in breast cancer, which, up until that time, had been based entirely on clinical criteria for response.

And furthermore, what occurred almost simultaneously with that was finally the invention of some serious drugs that could interfere with hormone action, most notably tamoxifen but several others that were synthesized at the time. And so rather than just having to oblate organs or use very toxic super pharmacological doses of steroids to treat patients with breast cancer, there was now a readily obtainable and usable oral therapy. And so there was a tremendous need to figure out how and why it worked. And a lot of people got into that field relatively rapidly. Bill McGuire being among them. James [? Whitless ?] being among them, myself for sure.

And all of us felt that this was an extremely important aspect. There was the clinical aspect, which became clear in the early '70s that there was, as you would expect, a very, very nice correlation between the presence of receptors and response. And that led up to the entire opening of this field of now that you could measure these receptors of how they worked, where they bound, what they did, what genes they induced. And so that became a lifetime exercise for many.

My impression is that before about 1970, endocrine therapy, which dated back the 1890s, was mostly done by the surgeons. Did you have to muscle your way into that field? Or were they openly agreeable that some guy who had never even did oncology would start treating breast cancer patients?

Well, I think that what was going on then, in England, there was a much greater delay in medical oncology as a field. And these patients were still treated by surgeons and radiation oncologists. I don't think there was any parallel issue in the United States. There were some very wonderful pioneering surgeons, but they didn't, I think, pretend to fundamentally want to get into molecular endocrinology. I don't recall that as being an area of conflict in terms of doing these kinds of studies.

And of course, in this country, we were unbelievably blessed by the extraordinary, absolutely extraordinary pioneering and organizational skills of Bernie Fisher, tremendous scientist, in his own right, a tremendous surgeon, but, even more importantly, the ability to really form the most effective, ragtag, co-operative group the NSABP, which was able, from its very inception, to do some of the most groundbreaking studies not just around hormone therapy, which they certainly did, but obviously as we all know about, differences in surgical care. And so--

You eluded to Dr. Carbone. My impression is the NCI, mostly, in those days, was all about leukemia and lymphoma, the so-called gang of five, MOPP and CHOP and Doctors Frei and [INAUDIBLE]. Who was behind you to move out and start taking care of patients with cancer in a more scientific basis? Was it just Carbone or were there other people at the NCI who [INTERPOSING VOICES]

Well, shortly after I got, there Paul left. He went to Wisconsin. And Doug Tormey, who had been nominally head of the breast group, departed. And so I was suddenly given an empty stage and said, well, why don't you do it? So within two years, I was running a program in which, the previous year, I hadn't even treated a patient. It was extraordinary.

But right about that--

I was-- that's a very good question and a slightly personal one.

About 30.

About 30, 31.

Yeah. Most 30-year-olds now are just starting their residency or their fellowship.

Right. And it is unfortunate that people with the most energy and most intelligence get increasingly pushed downstream. I mean, the age of first RO1s in this country is horrible, as we all know. And that's a major other problem that people need to address. But at that time, as you may recall, several groups were developing the first multi drug combinations for breast cancers. CMF, or as Johnny [INAUDIBLE] used to refer to it as CMF, and of course other variations with the MD Anderson regimens of so-called FAC chemotherapy, F-A-C, and other regimens that included vinca and prednisone. And so for the first time, reasonably active regimens were available for metastatic disease.

Where in the past, it had only been a handful of single agents, vinca, methotrexate, 5-FU. And at the same time, I think there were the extraordinary, a little bit later, the extraordinary first data that adjuvant therapy was successful. I mean, the studies done by the NSABP initially was single agents and then the CMF studies from Milan were extraordinary. I mean, breast cancer was and remains the most tractable of the solid tumors with the possible exception of testicular that we've treated in this country or anywhere.

Tell us about your lab work and how you established what you did, and then really interested in how you looked at what you were doing in the lab and said, jeez, this relates to my clinical work.

Well, thank you. As I said, when I had been working at Yale before I came back to the NCI. And at that point, at Yale, I was trying to develop models of gluconeogenesis in liver cells. It had nothing to do with cancer.

And so I arrived at the NCI, recruited by Paul, offered some laboratory space, and said, go to it. And I literally, literally scratched my head and said, well, what am I going to do now? And because I hadn't had a previous thing I was just going to expand on.

And because another great miracle that had been growing from very late '50s to the mid '60s was cell culture. I don't think people can now imagine how pioneering the results were to grow cancer cells and to get them to reflect, in any sense, the phenotype of human malignancy. I mean, now we take it for granted. But these were pioneers trying to figure out how to grow cells, Harry Eagle and Hamm and Dulbecco, and all of these other wonderful people.

So anyway, it seemed to me, wouldn't it be great, since someone had described a cell line that had estrogen receptor, I said to myself, what would be more straightforward than to figure out how you could manipulate these breast cancer cells with hormone therapies and figure out the mechanisms by using cell culture as a model for steroid hormone action? So I set about doing that. And after about six months, I succeeded.

And that was the good news. And ironically, the better news was that nobody else could reproduce it, including Dale McGuire. And lots of people said this was, frankly, garbage, that I was making it up. And so when eventually-- no. It was very upsetting. I don't think many people when they first start off and they have their first big set of papers, and I published this stuff in Nature and serious journals. And all of a sudden, everybody says, it's not true.

I remember giving a lecture at Harvard. And somebody at the end at the questions said, we just can't reproduce this data. We don't think you're telling the truth. I mean, how often you want to have that happen in your career? And as I said, what turned out to be very fortuitous was that we were right. And so eventually, that made things even easier for me in terms of my career. There's no question about that.

And a lot of people wanted to go to the NIH. I think it's now with so many wonderful-- what are there more than three dozen comprehensive cancer centers? But the United States in those days, there were just a handful. And most of them were doing leukemia and lymphoma, like Stanford, which certainly had almost no breast cancer program at the time.

And so people who wanted to work in breast cancer came to work with me. And lots of people wanted to get a BTA degree, Been to America. So I was fortunate to have some very outstanding people from Europe and Asia come to participate in my work.

And there was still the tail end of Vietnam. So some of the very best and brightest, if I could misuse that expression, people like Neil Rosen and Ed Gellman and Doug Yee and George Wilding, people who all became cancer center directors were people that I was very fortunate to have work with me. And I was pleasured to deal with them.

When did you say you were doing the lab models of cell lines and discovering how ER mediated the effects of estrogen? When did you start saying, let's take this over to the clinic? I mean, what was the first thing you did that you translated into the clinic?

Well, the first translational study I did when I was a fellow when I tried to do correlations of response to glucocorticoids in leukemic patients and ALL and AML. So I mean, I was used to going back and forth that kind of way. And we did a series of drug trials in breast cancer patients. I was seeing patients.

I haven't spoken much about it. But I don't know how to say that any other way whether it sounds modest or not. I simply love being a physician. I found that the main appeal of oncology was dealing with people at times of enormous obvious stress and disturbance in their lives. And I found that that brought out some of my best skill sets. And so I was anxious. I was always involved with patients like that.

One of the main trials that we got involved with involved Allen Lichter because Allen and I were endlessly discussing what was the right therapy for localized breast cancer. You may recall that Sam Hellman, the joint center, refused to be part of clinical trials looking at lumpectomy and radiation, as he was convinced, turns out correctly, that that was equivalent to doing mastectomy. And we felt, Allen and I, I think somewhat maybe arrogantly again, that we could do a single institution trial for lumpectomy versus radiation.

And we did. We ran a randomized trial of about 350 women at the NCI, a prospective randomized trial of lumpectomy and radiation versus chemotherapy. And of course, all of these patients became fodder for advanced disease trials and everything else we were doing. And those are some of the happiest days of my life working with Alan side by side in what may have been the first multidisciplinary clinic in breast cancer.

If I may, I'm going to interject. Allen Lichter, who started the department of radiation oncology at the University of Michigan, where I'm sitting right now, was my dean when I arrived here, became ASCO president at one point, and then was the ASCO CEO for years. Since this is an ASCO publication, if you will, I'd give him credit for all of that.

And well he deserves it. Well he deserves it.

Yeah. I can't agree more with that. That's for sure. The other thing I've heard you-- by the way, I've always wondered. How did you get 350 patients onto that trial at the NCI, since you've tended not to see walk in the door kind of breast cancer patients, right? So how did you?

Well, the NCI remember, everybody was treated free. So fortunately or unfortunately, given American medical economics, people who had a diagnosis would come to see us because they had no other option. We would pay all their travel and everything else. So we treated patients. And I have to tell you, up until last year when she died, I still had patients from that study who had followed me around the country to be treated.

That's a great story.

It's true. It's absolutely true.

So the other thing I've heard you talk about, and I think people should-- given the proliferation of medical journals now, there's one on every corner, I've heard you talk about the fact that you really have a hard time finding places to present your endocrine results, that the Endocrine Society didn't care about cancer. And AACR didn't care about endocrinology. ASCO didn't really exist almost in those days. Give us some stories about that.

Well, that's completely true. It's completely true. There was always a session in the Endocrine Society called cancer and hormones, which was late on Friday afternoon. And everybody had gone home. And AACR had the same thing. Because at that time, there just wasn't an obvious niche for cancer.

What began to make it more popular to both societies were when things like, quote, "growth factors," close quote, became more in evidence. And they clearly played a role in cancer. But clinical trials and clinical experience had no role in the Endocrine Society. And basically studies in molecular oncology just didn't seem all that attractive to AACR.

It wasn't like you couldn't talk about it. It just wasn't front and center what people were interested in. Everything goes through vogues periods. We're now going through an immunooncology voguish period. And I'm not trying to suggest that that's not extremely important and going to have endless value for people. But now, if you're doing almost anything else, you can't even write a protocol. It's true. It's true in some ways.

I was trained. [INAUDIBLE], who's an endocrinologist, was at the Dana Farber and told me that cancer is just endocrinology gone wild. In fact, I believe, in many respects, that's what precision medicine is all about is that we begun to take what you guys did 50 years ago and said, let's do it for all the diseases other than immunology, which is a different issue. I agree with you.

I think that that's a good point. I think that one of the fundamental differences between normal and cancer, however, is genomic elasticity. If you had psoriasis, and I put you on methotrexate. Then 10 years later, I doubled the dose, it would kill you. Because you never amplify the target gene, dihydrofolate reductase. And you remain sensitive throughout your entire life. Whereas doing that with a leukemic cell, in a couple of months, you'd be completely resistant.

And that is, in my mind, one of the shortcomings of so-called precision medicine in which you're trying to match a pathway, an oncogene, to a specific therapy. In that, oftentimes, these studies are in end stage patients with multiple resistant clones now has become endlessly clear from single cell sequencing studies. And I think that there is, I think, personally, slightly less to most efforts in precision medicine than most people think.

And I believe that it's amusing that precision medicine has come to include immunooncology, which has little, in my mind, to do with the initial way in which precision medicine was touted, which is find the oncogene. And we will give you the drug. And I think, by and large, that, except for some incredible successes like Gleevec for CML, hasn't really panned out.

Personally, I think what we're going to do is head back to what doctors Hall and Frei and [INAUDIBLE] taught us, which is that resistance is a heterogeneous issue, and we need to combine drugs. We just need to do it more thoughtfully than perhaps we've been doing in the past.

Couldn't agree more.

I want to change the paths for just a moment. To my knowledge, you are one of the few and maybe you were the first oncologist who's been both a cancer center director at Georgetown's Lombardi Cancer Center but also a chair of medicine. You've been at two major academic centers, here at the University of Michigan and University of Miami. Why do you think there have been so few oncologists who have been chiefs of medicine, chairs of medicine?

Well, your personal favorite institution, UT Southwestern, would be an example as well of a chair of medicine who's an oncologist.

Right.

But no particular reason comes to mind. I think that the skill sets and interests of a chair of medicine, at least as it used to be, up until maybe about 10 years ago, were someone who actually wanted to, A, have somewhat less of a research footprint, which would discourage some people, and something less of the same focus on curing a specific disease, which would certainly describe a cancer center director. And I think that exactly explains some of my clinical interest in becoming a chair of medicine at Michigan.

I went there, there are always push and pull reasons. The push reasons were that Georgetown was economically a disaster. And they had sold both the hospital and the clinical practice to a large non-profit community-based hospital. And I thought that would be, more or less, the end of the cancer center as I knew it in. And unfortunately, that prediction turned out to be, in many ways, correct.

So there was push issues. I just didn't want to officiate over the deconstruction of the cancer center that I had helped to build. And in addition, I felt clinically, I was raised in the era of great chairs of medicine. I was raised in the era of Don Seldon and Dan Foster and A. Magee Harvey, and people who knew everything and would teach at the bedside and knew everything about disease.

And frankly, I felt that breast cancer clinically, not emotionally and not from a research point of view, but clinically is relatively straightforward and not that complicated. And I wouldn't say I was bored. But I was looking for a new challenge. And I thought the notion of really trying to bring other areas to bear in terms of my research would be fun. And so I was thrilled to be chair of medicine. But I don't think that's necessarily the career path that many oncologists or any other subspecialist would want.

Which did you enjoy most, being cancer center director or being chair of medicine?

Unquestionably, being cancer center director here at Georgetown. It was the thrill of a lifetime. When I came here, there were three people in the division of hematology, oncology. Two of them immediately left.

And by the time I moved to Michigan, the Department of Oncology that I had created had more faculty than all of the basic science departments at Georgetown combined and more research money than all of the basic science departments at Georgetown combined. It was tremendously happy, very successful. And I felt we were doing really wonderful things. It was just a fantastic time, just like that, which is one of the reasons why I've come back.

And I was going to say, although Georgetown did fall on hard times. My opinion is grown back into a major institution. And I'm sure they're happy to have you back. So we're running out of time. I really just touched the surface of many of your contributions.

In addition to your scientific contributions, you really touched on it. You've been one of the most prolific mentors in our field in my opinion. I looked over your CV. I count at least six cancer center directors. I think five, four PIs and probably hundreds of others who are proud to have been under your watchful training eye, by the way, including myself, in our careers.

So of all the things you've done, your science, your administration, your mentoring, we've touched on all three of those. How do you want people to remember Mark Lippman when it's all said and done?

So there's a wonderful joke about that. These three guys are standing around saying what would they like to hear said around their coffin when they're dead. And one guy was a teacher, and he says, you know, I'd like them to remember what a wonderful teacher I was, how I helped people.

And another guy's a physician, and I'd like to hear if I'm lying in my coffin, them say, what a wonderful physician. He did everything for his patients. The third guy says, what I'd like to hear is, look, he's moving.

So it's hard to-- right. I am certain that the place that I feel most happy, it's not even a close call, is the ability to have played an important role in helping people's careers succeed. I mean, I'm something of a tough guy. But I have been, I feel, very willing to see people grow up and leave the nest and keep them nurtured and look after them for many additional years in their career and enjoy those relationships. It's incredibly enriching.

Well, I also have to say there are hundreds of thousands, if not millions of women who have benefited from the contributions you and your colleagues made 50 years ago at the NCI and since then. I've tried to make it clear through all these podcasts how much we owe all of you for what you've done and where we are now. And the reason we're doing this is so people don't forget about those things as we move into medical economics and some of the other things that I think are less fun.

So it's time to conclude here. I want to thank you for taking your time. And again, thank you for all you've done for the field, for those of us who've trained with you, and again, mostly for our patients. And I hope you've enjoyed this conversation as much as I have.

Very much, Dan. Thanks for including me in this podcast.

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 a 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.