Chapter 08: Discovering the FAC Regimen for Metastatic Breast Cancer

Chapter 08: Discovering the FAC Regimen for Metastatic Breast Cancer

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In this chapter, Dr. Hortobagyi describes his research into drug combinations for the treatment of breast cancer. He begins by stating that no one discovers anything new in science, but rather integrates and builds on knowledge created by others.

Dr. Hortobagyi says MD Anderson was an exciting place when he arrived in 1974, and the field was progressing. He also notes that the original pioneers were at the peaks of their careers or retiring, making room for new researchers. He summarizes philosophical differences between the Division of Medicine and Developmental Therapeutics, noting that the latter had visionary leaders who provided a unique environment for innovation. “Cancer was no longer a disease with no hope. “

Dr. Hortobagyi sets the context for his research by explaining that, at the time, important drugs had been discovered and needed a champion. His mentors were looking at chemotherapeutic agents, and he put them together and explored what would become the FAC combination treatment. Dr. Hortobagyi provides an overview of the drugs included in the regimen (Fluororacil, Adriamycin, Cyclophosphamide) and explains how they were selected and why that combination proved effective. The FAC regimen is still one of the most effective treatments against metastatic breast cancer.

Identifier

HortobagyiGN_02_20130107_C08

Publication Date

1-7-2013

Publisher

The Making Cancer History® Voices Oral History Collection, The University of Texas MD Anderson Cancer Center

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The ResearcherThe Researcher MD Anderson History The Researcher Discovery and Success Patients Cancer and Disease This is MD Anderson Understanding the Institution Institutional Mission and Values Healing, Hope, and the Promise of Research Overview Definitions, Explanations, Translations Understanding Cancer, the History of Science, Cancer Research The History of Health Care, Patient Care

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

Disciplines

History of Science, Technology, and Medicine | Oncology | Oral History

Transcript

Tacey Ann Rosolowski, PhD:

We’ll start up again. This is Tacey Ann Rosolowski, and today is January 7, 2013. The time is 1:14, and I am in the office of Dr. Gabriel Hortobagyi in Pickens—no, in the Cancer Prevention Building on the main campus of MD Anderson, and we are having our second interview session today. So, thank you for giving me this time.

Gabriel Hortobagyi, MD:

Thank you for having me.

Tacey Ann Rosolowski, PhD:



It’s wonderful, and we were just talking about how today we were going to begin with a focus on the history of—the evolution of your own research, and you were going to talk about kind of the big phases into which that was broken up.

Gabriel Hortobagyi, MD:

Right. Let me start by saying that in my view, very few individuals discover or invent anything. Most of us who have made some progress have taken information from various sources that were available at the right time, and we just saw the relationships and the interactions of these various sources of information, synthesized, and put them together. In other words, we stood on the shoulders of giants, as the old saying says, and we put together a package from various sources and moved the field forward that way. When I arrived at MD Anderson as a trainee, there were a number of very exciting things happening, and these exciting things provided incredible opportunities to make progress—progress for the field, progress for our patients, of course, and secondarily, progress for individuals who were willing to work hard and think imaginatively about the field. At the time I arrived, there was a generational change taking place within MD Anderson, and some of the original pioneers were either reaching the peak of their career or were already on their way to retirement. That opened opportunities in terms of employment and initiating new research without having necessarily to step over toes of other people who might have similar interests.

Tacey Ann Rosolowski, PhD:



Was there an intellectual and philosophical shift that that enabled as well, with the old guard moving out of the institution?

Gabriel Hortobagyi, MD:

Clearly there was. At the time I arrived—as we might have covered in an earlier conversation—there were two departments of medicine, for instance, and one department was a very well structured, very traditional Department of Medicine where I believe the major emphasis was on providing excellence in patient care, and there was much less effort and passion dedicated to innovation. The other department, which was called Developmental Therapeutics, was much more focused on innovation and moving the field forward with much less emphasis on just providing traditional care. That meant that that department was not interested in excellence in patient care. It’s just that was not the primary driver of the department, and the second department was much more recent. It had just been established a few years earlier. It was populated by a lot of young people who were bright-eyed and bushy-tailed and wanted to move things forward and had a fairly visionary leadership, too—Dr. Freireich and Dr. Bodey and Dr. McCready and others—and I happened to join that department as a trainee.

That provided me not only the opportunity but also the environment to focus on innovation and focus on how to make things better. And as I may have mentioned earlier, it was the first time we were really thinking of cancer in terms of we can take care of this. We can control it. We can perhaps cure it in a number of circumstances, and we don’t need to look at cancer as a uniformly fatal disease where there is no hope, which was the prevailing attitude in many areas.

Gabriel Hortobagyi, MD:

The second part is that around that time, a number of very important new drugs were being discovered: the anthracyclines, adriamycin, epirubicin, and daunorubicin were just coming online. They were in phase II studies. Cisplatin was just in phase I finals at that time. Vinorelbine was a new drug. Tamoxifen was a new drug. All of these were still looking for someone, some champion to move them forward. The third part is that we had a group of very bright individuals who were my immediate mentors—Jordan Gutterman; J Freireich, of course; Jeff Gottlieb; and others—who were so totally focused on moving the field forward that you couldn’t possibly think of anything else. When you put all of this together, then I had the opportunity of putting together a combination. I can’t claim total credit for that because it was really a group effort—the fluorouracil-doxorubicin-cyclophosphamide combination, also known as FAC—which was first put together in this institution. I was one of the lead investigators in making sure we found the place for that in breast cancer.

Tacey Ann Rosolowski, PhD:



0 Can you describe to me what were the characteristics of these drugs that made them so effective and that made them so effective together?

Gabriel Hortobagyi, MD:

The anthracyclines—especially adriamycin, which is more relevant to our discussion—the anthracyclines are a group of antibiotics that are produced by a group of fungi, and they have a very specific target today we know, which is the inhibition of topoisomerase II, which is critically important for processes of cell division and DNA repair. By interfering with that process, they produce lethality in cancer cells and in other cells. These drugs were found to be some of the most effective drugs not only in breast cancer but in lymphomas, in Hodgkin’s disease, in gastric cancer, in a variety of other tumor types. Fluorouracil is one of the most commonly used drugs—or was at that time—and it was a broad-spectrum cytotoxic agent with a significant efficacy in breast cancer, in colorectal cancer, in lung cancer, and so on. Cyclophosphamide is a classical alkylating agent which is much better tolerated than the original alkylating agents like nitrogen mustard and busulfan and others. And again, it is a broad-spectrum antibiotic that is quite effective in breast cancer, in lymphomas, in lung cancer, et cetera. And what makes these three drugs such a natural combination is that they have different mechanisms of action. They have largely non-overlapping toxicity, and they have different mechanisms of resistance; and therefore, there is every reason to believe that by combining them, not only would one get a higher response rate by perhaps targeting different cell populations within the same tumor but that there would be a built-in mechanism to prevent the evolution of drug resistance against any of them because evolving drug-resistant populations would be attacked—one drug would be attacked by the other two—and that one could do this with almost full doses because the toxicities were not overlapping. One was not just adding toxicities by adding one drug to the other.

Those were important characteristics of this particular combination, and when put in practice, well, it turned out to be a very, very effective regimen. And arguably, it is even today one of the most effective combinations—certainly in the area of breast cancer. We developed this in metastatic breast cancer, and the initial analysis that I did suggested that two out of three patients with metastatic breast cancer had an objective response to it—meaning a greater than fifty percent reduction in tumor area—and that some of them had what we call the complete clinical remission with the disappearance of all physical and radiographic evidence of metastatic disease. So that was very encouraging.

Tacey Ann Rosolowski, PhD:



Can I ask you how long—what was the response time required to see those results?

Gabriel Hortobagyi, MD:

In metastatic disease, on average it takes about nine weeks to start to see an objective response. Now that means reaching the criteria by which we define partial remission or greater. But you start seeing responses much earlier, sometimes within the first three weeks. Sometimes in patients who were symptomatic, we would see—we would experience pain relief within just a couple of days. The rapidity of the response was quite notable. Now there is a delay between a biological response and until one can document that by radiography or nuclear medicine or some other imaging methods, so that’s why it takes about three cycles or about nine weeks, to document an objective response. But this is a very effective regimen. Once we started to see how effective this regimen was in metastatic disease, then we started to think along several lines of research.

Tacey Ann Rosolowski, PhD:

Before you do that, can I ask you how did you come upon this particular group of drugs from those three categories?

Gabriel Hortobagyi, MD:

Prior to the early 1970s, essentially all of chemotherapy for breast cancer, which was very modest, was based on single agents. You used one drug at a time. There were a few exceptions. There was a pioneer from New York, Ezra Greenspan, who put together two and three drugs and obtained some improved responses. But brilliant as he was, he only published in the private journal of the Mount Sinai Hospital in New York, so it never reached a broader circulation or readership. Another very bright individual from that time in Roswell Park, Richard Cooper—who is in one of those photos up there and is a good friend—he put together a five-drug combination with cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone, which later became known as the Cooper Regimen, and he presented his very exciting results at an ASCO meeting, but he never went beyond an abstract. He never published a full paper. So essentially combination chemotherapy was nonexistent, for all practical purposes, in the early 1970s.

But we already knew that there were a number of drugs—not many, mind you—but we knew that alkylating agents were effective against breast cancer—somewhat modest efficacy, but they were effective, and 5-fluorouracil was effective against breast cancer. The most exciting new development when I arrived was adriamycin. That was arguably—and even today—one of the two most effective drugs against breast cancer. At that time it was clearly the most effective drug against breast cancer, and there were some others which were of marginal efficacy: vincristine, the corticosteroids, the nitrosoureas, perhaps mitomycin C. But those were either much more toxic or much less effective. These three drugs were clearly the ones to pick on. A fourth drug that would have been perhaps an important contribution was methotrexate, but methotrexate has overlapping toxicities with both 5-fluorouracil and with adriamycin, so it would not have been a good choice. By deduction and elimination, these three drugs became the winners, and there was some previous experience combining 5-fluorouracil with cyclophosphamide, and then there was some pilot experience combining adriamycin with cyclophosphamide, so then it was a natural step to go to the three-drug combination.

Tacey Ann Rosolowski, PhD:

Well, I'm curious. How did that happen? I mean, did you sit down with your group of collaborators and say, “Let’s put all the pros and cons on the table” for each of these? What was that process like?

Gabriel Hortobagyi, MD:

There was a continued process of communication and looking at the drugs that existed at the time and the common solid tumors that we had in front of us to deal with, and there were some limitations in terms of what we could address—one, because a very common solid tumor, prostate cancer, was entirely in the hands of the urologists. The medical oncologists did not see prostate cancer in the early 1970s. The colorectal cancer seemed largely resistant to many drugs, or at least that was the reigning belief. There was not much enthusiasm for getting into colorectal cancer. Melanoma seemed highly resistant. Sarcoma seemed highly resistant. Breast cancer was sort of the poster child of let’s develop combination therapy, because after the lymphomas, it seemed to be the most responsive type of cancer, and we had in front of us the example of lymphomas. The group of Dr. Freireich when they were at the NCI and then later with credit claimed by Vincent DeVita, they put together MOPP and other combinations that ended up being curative. At that time, we were thinking we can do the same thing in breast cancer. We have now three or four drugs that are substantially effective that we can combine, and we think that we can combine them, so let’s put them together. The initial idea was to administer each of these drugs once per week. That didn’t work out quite well, so it turned out we could give adriamycin best once every three weeks and cyclophosphamide best by giving it once every three weeks. With 5-FU we wanted to give it every week, because at that time it was thought that that was the best regimen.

Tacey Ann Rosolowski, PhD:

So you didn’t mix all the drugs together in one cocktail.

Gabriel Hortobagyi, MD:

No, no, no. But it turned out that because of myelosuppression—a drop in blood count—it was not possible to give 5-FU every week. We could do it the first week and the second week, and then we had to skip the third week, and this was arrived at largely by empirical testing. Now it would have taken us much longer today because of the regulations and because of all the restrictions about how you go about research. At that time you could take drugs—those that were commercially available—and you could administer them in any way that you considered was safe and appropriate. You could experiment with schedules and doses, and adding adriamycin to that was relatively easy. We worked this out in a relatively short period of time—just a few months—by treating some with a one-dose schedule and the next few with another dose schedule, and there was no encumbrance to that type of research. And then once we came up with the combination, then we wrote a protocol, a clinical trial. Then we tested it formally.

Tacey Ann Rosolowski, PhD:



Who was involved in this first push of the research with you?

Gabriel Hortobagyi, MD:

Jeff Gottlieb, Bob Livingston, who was an assistant professor at that time, and George Blumenschein. That then went forward. In the meantime, my immediate mentor was—or one of my immediate mentors—was Jordan Gutterman, and Jordan Gutterman and Evan Hirsch were heavily focused on harnessing the immune system, immunotherapy of cancer. That was the Holy Grail of oncology at that time, and there was much, much excitement about that. Our initial emphasis was on the administration of BCG, or Bacillus Calmette-Guerin, as a way to enhance the immune reaction of the host. One of my priorities at that time was to add BCG to this new redeveloped combination of FAC, and some of my early papers were based on that. The initial results seemed very promising. Later we put it through more formal tests, and the results were much less conclusive. And eventually we abandoned that line of research, but that kept me busy for several years.

Tacey Ann Rosolowski, PhD:



Were there important lessons learned from that period of experimentation?

Gabriel Hortobagyi, MD:

Very. Secondarily we figured out that the more a patient reacted to the administration of BCG— the stronger the local reaction—the better the patient would do. Initially we thought that was the effect of BCG. Later we figured out that it was more a question of the patient’s immune status baseline. And in fact, I did a series of studies in which I looked at baseline immune response by skin tests and other immunological tests to look at the patient’s immunocompetence. And it turned out that those who had the greatest immunocompetence at baseline lived longer and had a higher probability of response to chemotherapy and longer duration of response to chemotherapy. One starts with one hypothesis and sometimes ends up with another. But that observation certainly ended up twenty years later guiding many of the current examples of the immunotherapy in breast and other cancers.

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Chapter 08: Discovering the FAC Regimen for Metastatic Breast Cancer

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