BROADCASTS.com

b"

Dr. Daniel F. Hayes is the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center. Dr. Hayes\\u2019 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.

\\xa0

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 Cancer Stories. I'm Dr. Daniel Hayes. I'm a medical oncologist, and I'm a researcher at the University of Michigan Rogel Cancer Center. And I'm also the past president of the American Society of Clinical Oncology. Over the last and now the next several podcasts, I've been really privileged to be your host for a series of interviews with the people I feel are the founders of our field.
Over the last 40 years, I personally have been fortunate to have been trained and mentored and I've also been inspired by many of these pioneers. And it's my hope that through these conversations. We'll all be equally inspired by gaining an appreciation of the courage and the vision and the scientific understanding and the anecdotes that let these men and women to establish the field of clinical cancer care over the last 70 years. By understanding how we got to the present and what we now consider normal in oncology, I think we can also imagine and work together towards a better future for our patients and their families during and after cancer treatment.
Today, I'm really pleased to have my guests on this podcast Dr. Norman Wolmark, who was his mentor and longtime colleague, Dr. Bernard or Bernie Fisher, was responsible for the unbelievable success of one of the most influential cancer cooperative groups in the world, the National Surgical Adjuvant Breast and Bowel Project, or the NSABP, which of course, in recent years has now been merged with two other corporate groups to become the NRG.
Doctor Wolmark as a professor of surgery at Drexel served as the executive medical officer from 1979 to 1994 during Dr. Fischer's leadership of the NSABP. And then he became the chairman and PI of the group until 2004 when he assumed the same role with the merger into the NRG. The NSABP is generally credited with what is now called de-acceleration of therapy, in particular of local therapy of breast cancer by applying the scientific method to compare a modified radical mastectomy to radical mastectomies and subsequent breast conserving treatment a modified radical mastectomy, as well as testing the concept of sentinel node mapping, which we now use routinely.
NSABP was also one of the pioneer groups to test the value of adjuvant systemic therapy. They started with adjuvant chemotherapy, comparing L-phenylalanine mustard, or L-PAM to nothing in the 1970s, and later, tamoxifen versus nil. Other successes of the NSABP include one of the first trials or adjuvant trastuzumab.
And further, NSABP was the first to report the prognostic value of the genomic test to guide the use of adjuvant chemotherapy in ER-positive breast cancer. Incidentally, it also conducted the largest and the most definitive set of studies of chemo prevention, first with tamoxifen versus nil, and then later, comparing raloxifene to tamoxifen. Not just breast cancer-- in gastrointestinal malignancies, the NSABP made seminal observations regarding radiation for rectal cancer and adjuvant chemotherapy in colorectal cancers.
Dr. Wolmark himself has published over 300 peer reviewed papers, numerous other commentaries and reviews, and frankly, I started to list your honors, Dr. Wolmark, but I ran out of space. You've just had too many to count here. I think it is safe to say that the reduction of both mortality and toxicities related to breast and GI cancers over the last four decades, coupled with improvement on how we treat people, is in large part due to the brilliance and the courage and the hard work of doctors Wolmark and Fisher.
Most importantly, I think they showed so many of us the importance of challenging dogma, for example, how study and thinking in breast cancer and applying the scientific method to clinical research and practice. [GASPING] I have to take a deep breath, Norm. Welcome to our program, and thank you for joining us.
Well, thank you, Dan. I think after that glowing and complimentary introduction, which was far too generous, probably the most strategically sound decision that I could make is to thank you and to terminate this discussion, because I don't think that I can possibly improve on it. But I don't suppose that that's the purpose of this endeavor here.
Yeah, no. People aren't tuning in to hear me. They're tuning in to hear you. And this is hero worship on my part. I want to start out with your background. I know you grew up in Montreal. You graduated from undergraduate, medical school, and later, you did your surgical training at McGill. What were the circumstances that your family was in Canada? And what got you interested in medicine and, specifically, surgery?
Well, that's an interesting question. I did not grow up longing to become a physician. As a matter of fact, my interests at McGill, certainly during undergraduate school, included biochemistry. And I was in the honors biochemistry program and was going to pursue a career in nucleic acid research. And at the last moment, I had a change of heart and decided to go into medicine at McGill.
And McGill was not an embracing environment for surgeons. I think surgery, certainly in our era, was regarded as a sub-medical species. And it wasn't until my internship and early residency that I embraced the possibility of developing and evolving a career in surgery.
Was that attitude out of also having been at McGill-- long before you were there, I know, but most places were dominated by the surgeons. And then medicine came along after that-- Mayo Clinic, for example. Do you know? Was this an outgrowth of Osler's influence?
Well, I don't know that it was an outgrowth of Osler's influence, but it was certainly difficult for us to escape Sir William Osler. I think at the graduation after our second year, we were provided with a leather bound copy of Aequanimitas, which of course, nobody read, because medical students are not interested in the history of medicine. It was only years later that I read most of Osler's non-scientific works.
That's interesting. So then you went to Pittsburgh to do your surgical residency and then two years at the NCI and a year at Memorial. But then, you returned to Pittsburgh. Why Pittsburgh in those days?
Well, what drew me to Pittsburgh in 1973 was my interest in clinical trials. And in 1973, there was a lot of excitement going on in clinical trials and breast cancer directed by Bernie Fisher and the NSABP. So that was something that attracted me, that one could apply the scientific method to evolve therapy. And this was something that I desperately wanted to participate in as a result of my background in basic research and biochemistry.
So tell us about the heady days in the early '70s and even further back, if you'll recount sort of Dr. Fisher's history as well, of starting the NSABP. What was his vision? What was his plan? Why did he do that? How did you get involved?
The whole evolution of cooperative groups and in particular, the NSABP, was an outgrowth of the initiative of the National Institutes of Health and more specifically, I think, to Bernie Fisher's mentor, IS Ravdin, at Penn. And that led to the creation by the NIH of the Cancer Chemotherapy National Service Center. And this was started by three surgeons and Michael Shimkin at the NIH, who was a medical oncologist, or what was then called a chemotherapist.
And from that grew a number of disease-oriented initiatives called the surgical adjuvant chemotherapy projects for specific diseases, breast being one of them. And this was 1957. And by 1958, the NSABP had randomized its first patient. And certainly, Bernie Fisher was amongst the founders of the NSABP and then, of course, became chairman of the group in 1967 and moved it to Pittsburgh in 1970.
What did it take to get a bunch of surgeons to believe that more than just surgery was important?
The group started in a modest fashion. There were 23 institutions. And I think it's certainly an enormous credit at Bernie Fisher for demonstrating that a cooperative group could indeed be cooperative, with multiple heterogeneous surgeons joining under the rubric of the NSABP to evolve the state of the art breast cancer and challenge existing dogma.
One of my first meetings, Dr. Fisher and Dr. Irvin of New York City were in a debate that I thought was going to get into a fistfight, with Dr. Fisher trying to explain the systemic therapy of cancer and that it was more than just surgery, and Dr. Irvin believing if you did super-radical mastectomies, you could cure more. You must have been in the middle of some of those discussions as well.
I was, and remember them, and remember the acrimony, the hostility that existed at that time. As a matter of fact, there were societies that were created to counter the influence of the NSABP. The retreat from radical mastectomy was highly contentious. And of course, the debate of the two mutually exclusive hypotheses was certainly extant in Halsted's era.
But Bernie Fisher determined instead of debating the issue to test the two mutually exclusive hypotheses using the scientific method, namely the randomized prospective clinical trial, which convinced surgeons that variations on the theme of operative nuance were not going to increase survivorship, that breast cancer was a disease with systemic components at its initiation, and the retreat from a radical mastectomy and the ascent of systemic therapy are inextricably intertwined. And they are so largely because of the efforts of Bernie Fisher and the NSABP.
This is an interview with you, except that you know Bernie Fisher better than any of us-- who, incidentally, turned 100 years old in August of this year. What were the driving forces for him to think this way? Do you know? Was there a sudden aha that systemic therapy ought to be as important as the surgery? I know he did some preclinical studies to suggest this. Can you give us more background of what he was thinking and how he got there?
Well, when I first joined him in 1973, it was a unique environment. There was a continuum between the laboratory and the clinic. And hypotheses were generated in the lab from murine models and applied to clinical research, which we now call translational research. And certainly, I think he was influenced in many ways by the preclinical work that he did in murine models on metastases and multiple other observations to challenge the sanctity of the radical mastectomy, which was based on the belief that breast cancer was a local, regional disease and spread in a logical, predictable, stepwise manner, again, along fascial planes. This, of course, to scientists, was something that did not stand up to a solid review of the data.
Through the years, I've picked up many pithy comments from Dr. Fisher. One of them is that-- what was it? In God we trust. And for everything else, we like data, which I always thought was a great statement, something to that effect. The other was, you may be logical, but breast cancer is not. That really has stuck with me through the years, which is, it doesn't follow a logical string of linear progression. But rather, it becomes systemic, or it doesn't, which I think changed the field.
Well, Bernie always challenged existing dogma that was based on empiricism. I think Bernie taught us to challenge the individual who ascends to the professorial pulpit armed with a retrospective case series. And based on personal charisma or the institution that that individual represented, such an individual was able to influence the way a disease was treated for decades and then close to 3/4 of a century. Challenging that dogma, insisting that therapy be evolved based on data rather than retrospective case series, I think, is a lasting contribution. He blazed the trail for the rest of us.
Since you were there for a lot of this, how about some of the other luminaries of the time? Dr. Crile had a lot to do with the early thoughts that maybe you didn't need to do mastectomy. Can you enlighten us on some of the other folks that were some of the early pioneers in the field?
There were certainly proponents of lesser operative procedures starting with [INAUDIBLE] and in the UK, Vera Peters, in Canada, Barney Crile, or George Crile, Jr. at the Cleveland Clinic. But again, these were based on anecdotalism. There were very few randomized prospective trials challenging the sanctity of the radical mastectomy. There were some-- Sir Hedley Atkins, the Guy's Hospital trial comparing breast-preserving versus mastectomy, a trial that had few patients and was reported, I think, in 1971 was a case in point. And then Umberto Veronesi with the quadrantectomy study, which was reported in 1981, preceded B-06.
But certainly, B-06 had an enormous impact in 1985. And I think to Bernie's credit, he was able to convince his colleagues, even his detractors and his coevals of the value of breast preservation. But more importantly, I think he was able to convince surgeons of the biologic behavior of breast cancer with its systemic components.
Yeah, I agree. I remember that paper. Actually, I remember most your papers.
B-04 for was the predecessor. And of course, if there is a Rosetta Stone for the NSABP, it was comparing radical mastectomy to total mastectomy, which was a heroic trial to have initiated in 1971. If there is a bellwether turning point, it was B-04. This was the trial that truly compared the two mutually exclusive hypotheses to enormous, enormous resistance by the surgical community. And the paradox was that the 23 institutions that participated in the NSABP were run by surgeons.
I came into the field in 1982. I have seen maybe three radical mastectomies in my life based on the fact that B-04 was beginning to change that whole field. And the three or four patients I saw had horrendous qualities of life because of that radical mastectomy. So I think our listeners, the younger ones, need to understand how courageous this was.
Let me ask another question. I don't think you were part of it then, but as Dr. Fisher began to, then, think about adjuvant chemotherapy, why L-PAM? Most of the people listening to this probably have never heard of L-PAM, let alone used it. Why was that chosen as the chemotherapy to use in the first trial?
Well, that's an interesting question. CMF was being developed at the NCI-- Paul Carbone, Vince DeVita, George Canellos. And L-PAM was an oral agent. And we speculated, sotto voce, of course, Bernie and I, that the reason the NSABP got L-PAM was that it was oral and could be given by surgeons, whereas the CMF, which was more difficult to administer, went to Gianni Bonadonna, who reported on the CMF data in the adjuvant setting a year after the L-PAM data were reported in 1975.
Ironically-- correct me if I'm wrong-- but I think the relative benefits of both were almost identical. And the reason L-PAM fell out of favor was the secondary leukemias. Is that your perception?
Well, L-PAM fell out of favor, certainly. We did L-PAM, then L-PAM 5-FU, then L-PAM 5-FU plus doxorubicin in a stepwise, sequential manner. I think CMF was embraced. Had there been a direct comparison earlier on, perhaps L-PAM would have had a role. But I think it faded away. And it faded away for us largely because when we compared CMF to four cycles of AC, which could be given in a much shorter time, there was no difference. So AC became the standard, certainly for us.
Moving on a bit, as I've already-- another of Dr. Fisher's statements that I've lived on is that the hallmark of a good clinical trial is that it raises more questions than it answers. I love that because it means you have to keep thinking. Can you give us examples how you and Dr. Fisher started designing the next trial as the first one was starting to finish, and how that led, one way to the other? I've always been struck by the fact that the NSABP has been more linear in its trial design than most of the other cooperative groups.
Well, it was a continuum. The next trial was based on the results from the previous trial or the anticipated results from the previous trial. A case in point, B-04, total mastectomy, where lymph nodes are not fulgurated, left behind completely untreated, compared to radical mastectomy, where they were removed. 40%, it turned out, of the total mastectomy group had histologically positive nodes. And yet, the outcomes were the same, which supported the use of systemic therapy, that patients were failing not because inattention to operative detail, but because they had systemic metastases.
Well, you can ask, how did you transpose this data or know about this data to start your next trial? Well, in that era, the results were available to us in real time. We had a magnetic board, for example, for B-04, where every patient that was entered into the study, of course, anonymized, was on that board, and we could see the treatment failures in real time. So we had a pretty good understanding of what the results were when B-06, for example, was started, and certainly when the L-PAM trial was initiated.
To us, in that era, alpha-spending meant buying a suit at Bergdorf Goodman. It's only later that these restrictions, appropriately so, were initiated. So we were able to be very nimble in transposing the data from one trial to formulate the hypothesis for the next trial. And that led to, I think, a very elegant, sequential, logical, stepwise series of trials, which I think in this era, could not be conducted.
Did you ever get concerned that you were jumping ahead to the next trial with insufficient follow-up with the last one, and you'd get ahead of yourself in terms of unexpected toxicity showing up or, for example, in the deacceleration of therapy, that in fact, you were wrong, and then you had a bunch of patients that you had given less than enough therapy? I can't think of the fact that you have. But was that a concern as you were designing these?
Every clinical trial is a concern. And yes, there was a concern. But we believed that we were basing these trials on objective data, data that were generated through clinical trials and the scientific method.
So let me ask another question, because I was never in the NSABP, but I was always struck by the fact that your statisticians sat at the table and thought as much about the biology as they did the p-values. Do you want to talk about some of the statisticians you've had the chance to work with?
Absolutely. I think that's an accurate description. Carol Redmond was the first statistician with whom I came in contact and was an integral part of clinical trial development, discussing not only sample size, p-values, interim analyses, but also the biology of the disease and what the biologic end points were going to be, and what the ancillary end points ought to be, and calculate appropriate sample sizes to answer these questions. We were very fortunate to have outstanding biostatisticians who were giants.
Sam Weiand, who followed Carol Redmond, who was at the University of Pittsburgh, went to the Mayo Clinic, and returned to us around 1994, '95, and John Bryant, who was absolutely instrumental in the joint analysis for the Herceptin trials, B-31 and N9831, who was a driving force, and was certainly a driving force behind the development of the Oncotype DX genomic profiling. These weren't simply numbers people. They were colleagues. They were part of the assault on the hill.
I have to jump in for two reasons. One is I never worked directly with John Bryant, but I can't say how many times I called him and said, what do you think of this? because I knew he would understand the biology as well as the statistics. I miss him dearly. He sadly passed away about a decade ago.
As do I.
The other is, as you know, we lost Jim Holland this year. My first presentation at CALGB, Dr. Holland was sitting in the back of the room and yelled from the back of the room, because he never used a microphone, not unlike my colleague on the line right now, by the way. Dr. Holland yelled from the back of the room, Hayes, if you need a statistician, it's not worth doing. And I said, well with all due respect, Dr. Holland, and there's a lot of respect here, I have to disagree with you. Did Dr. Fisher get along with the statisticians the way you have? Did he feel that this was a two-way street? Or were there times he said, my way or the highway?
There's always robust dialogue and discussion. I think that both Bernie and I embraced our statisticians as colleagues. I have to be very careful. This was not unwelcome embracing. But they were always an integral part of developing and analyzing the protocol. And they were colleagues. And certainly, Bernie had that approach and philosophy as well.
So let me, perhaps, describe in 1973, when I first arrived, what struck me as extraordinary. There was passion, excitement, drama. We weren't sure where we were going. But we knew we were getting there fast. And we embraced the journey, the quest. And that was an extraordinary time where we knew that the standard of care was going to be changed. We couldn't predict the outcomes, but we knew that what we were doing at the time would have a lasting impact on the field.
Actually, that was my question, which was, did you realize what you were doing in the late '60s and early '70s was as exciting as it was? Sometimes, I think we're in the middle of something, and we don't realize how it's going to turn out. And you've just answered my question, which was it must have been years--
It was challenging the basic sanctity of the dogma, the tyranny that existed at the time. And that, in itself, was a courageous and extraordinary thing to do.
And I have to say because of that work, and others, but we've seen a remarkable reduction in mortality due to breast cancer over the last 30 years, probably by more than a third, not quite half. And it's because of these kinds of challenges of dogma and courage to move forward. So I think we all owe you and Dr. Fisher and those who were involved in the early days, then also in the other groups, just an enormous debt of gratitude.
My final question to you, Norm, and everybody asks this where did you get your style of presentation? I've argued, although I know you're Jewish, you could have been a Baptist minister. Where did this come from?
I have no idea.
Everybody loves it.
Well, that's certainly very gracious of you, Dan. I've certainly, in the era of protocol B-04 and B-06, I have been summarily booed by an audience in unison. So that may not be a uniform perception.
Well, I hope that our listeners who are driving to work or having their morning cup of coffee and listening to this have enjoyed it. I certainly have. Thank you for being so gracious and taking the time to do this. Thank you for all your contributions to the field and for mentoring so many, including myself, frankly. And I consider you a great mentor and a great friend. So I appreciate it deeply.
Thank you, Dan. It's been my privilege.