Chapter 19: A New View of Breast Cancer and Research on HER2 Positive Breast Cancer

Chapter 19: A New View of Breast Cancer and Research on HER2 Positive Breast Cancer

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In this chapter, Dr. Hortobagyi talks about the next stages for breast cancer research. He first provides a snapshot of how breast cancer was viewed ten to fifteen years ago. He then traces the many forces that came to together to revolutionize the understanding of the disease, which is now seen as many chemically and genetically unique diseases, rather than a single phenomenon. The factors Dr. Hortobagyi lists are a new understanding of the significance o estrogen receptors in cancer cells, the completion of the Human Genome Project, the completion of gene expression profiles of various breast cancers, investments by the government in the ‘war on cancer,’ and the pharmaceutical industry’s investment in cancer treatment drugs. By the mid-2000s, all of this work had led to an explosion of knowledge about the significance of breast cancer subtypes.

Dr. Hortobagyi then talks about his work on HER2 positive breast cancer. He notes that through his work on Herceptin, he was involved in advancing the understanding of this breast cancer subtype. He describes how he organized yearly by-invitation meetings of researchers: this event led to many collaborations that advanced the field. Dr. Hortobagyi then explains that his role in research changed. With more involvement in administration, he did more coordinating and facilitating of research for others. He notes his involvement in national organizations. He explains that in 2005 he joined the Southwest Oncology Group and became chair of the breast cancer committee, responsible for coordinating research. Dr. Hortobagyi comments on how important such organizations are for extending MD Anderson’s reach and to generate enough participants in clinical trials.

Identifier

HortobagyiGN_03_20130123_C19

Publication Date

1-23-2013

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 Discovery and Success Overview Definitions, Explanations, Translations Discovery, Creativity and Innovation Professional Practice The History of Cancer Research and 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



Okay. To answer that, let me go back about fifteen, twenty years. I’m talking about the early part of the 1990s.

Tacey Ann Rosolowski, PhD:

Uh-hunh (affirmative).

Gabriel Hortobagyi, MD:

So up until then we really thought of breast cancer as a disease of the breast—cancers that may grow into different morphological appearance and microscopic image. But they were essentially just breast cancer. Then while the estrogen receptor was discovered probably twenty years earlier, there was a lot of argument about the value of the estrogen receptor in the 1980s and even into the 1990s, in part fueled by technical difficulties in measuring it appropriately and testing for it and by poorly designed research projects that led many to conclude that it had no value. But then several things came together in the early 1990s. One was that we increasingly became confident that the estrogen reception and secondarily the progesterone receptor were truly important and that those breast cancers that expressed higher quantities of estrogen receptor were a different animal from those that did not. Simultaneously, in coming in part from work related to some of the early work that Dr. Mendelsohn had done with the epidermal growth factor receptor, there were observations about HER2. HER2 was another biomarker. It is also a cell surface receptor. That suggested that those tumors that had a lot of HER2 on their surface or that had many copies of the HER2 gene inside the nucleus behaved differently. They were much more aggressive than those that did not. They tended to be estrogen receptor negative. So that then came up with a—like a third different type of breast cancer. While there was not a single date when we decided that breast cancer was no longer a single disease, it was again this dawning of this insight of we no longer think of breast cancer as being as single disease and all treatment—one treatment fits all. This happened somewhere during the ’90s. I remember some of the times when I started to talk about this in public as I was invited to give lectures and grand rounds and whatnot. It was a gradual evolution.

The people at the beginning started to look at me like, where did you get that from? And it was only within the smaller club of breast cancer experts where this sort of became an understood thing. But it wasn’t something that anybody really discovered. It was that just slow coming together of concepts from different sources. Then in 2000, of course, came the completion of the Human Genome Project. In the mid-1990s, Dr. Pusztai, and Dr. [Robert C.] Bast and Dr. [Gordon B.] Mills and I started to work on an exclusive collaboration with a company called Millennium. These were the early days of gene expression profiles. It was sort of revolutionary, but we were just taking the first steps of this and trying to figure out what to make of it. That also underlined the importance of the estrogen receptor, and it wasn’t just the estrogen receptor. But it became apparent that those breast cancers that express or overexpress the estrogen receptor also had a different expression of some 600-700 other genes from the estrogen receptor negative tumors. So then we had much more ammunition all of a sudden, and I’m talking now about the last 1990s before the Human Genome Project results—that there were these differences—these fundamental differences in the biological underpinnings of these various breast cancers and that we needed to think differently about them. In the meantime, of course, we developed newer hormonal therapies, so the aromatase inhibitors came around, the LHRH analogs came around. Then on the other side for the HER2 positive breast cancers, Herceptin came around. Then lapatinib came around. So then it was an entirely new ball game. Then soon after the Human Genome Project, some scientists—at that time it was in Stanford, but the lead scientists moved to UNC—published a very influential paper in which they looked at several dozen primary breast cancers, and they looked at the latest technology and gene expression profiling and were able to identify four or five fairly different breast cancers based on their gene expression profile. Among those five were the three that we had sort of become comfortable with, which was the estrogen receptor positives, the HER2 positives, and those that expressed neither the estrogen receptor nor the progesterone receptor nor HER2. Then was another category there that nobody knew what to do with—and even today we don’t know what to do with—which was a normal-like thing, which is probably an artifact of the technology or the way we obtain tumors. So then that now gave us sort of two overlying or overlapping ways to look at breast cancer: one by gene expression profiling and one by looking at simple pathological techniques, such as immunohistochemistry and FISH. We identified very similar subgroups of breast cancer—subtypes of breast cancer. From the mid-2000s—I’d say 2003, 2004, 2005—there has been this explosion of knowledge and understanding about what these subtypes mean. And we clearly think of breast cancer today as very different syndromes—very different diseases that just happen to start in the breasts’ tissue, but they are biologically different. They behave differently. Their sensitivities to existing treatments is different. So it’s quite a revelation. So that was another emerging paradigm. Then more recently, these small versions of that start to pop out more and more frequently, in part because the enormous investment of money that this country has made in the war on cancer and the enormous investment that pharma has made in developing new therapeutics for cancer—is just starting to come to fruition, and there is this incredible proliferation of knowledge and publications and new drug candidates and new test candidates that I think is going to be enormously influential in what the future of managing breast cancer is. So it’s very, very exciting.

Tacey Ann Rosolowski, PhD:

How do you see your own research path coalescing within that or out of this new context?

Gabriel Hortobagyi, MD:

Well, in several different ways. First of all I was very much involved in the early development of the HER2 story.

Tacey Ann Rosolowski, PhD:

Uh-hunh (affirmative).

Gabriel Hortobagyi, MD:

And the development of Herceptin. In fact for about ten, fifteen years—very early on I organized every year a translational research meeting about HER2 and about Herceptin and similar anti-HER2 drugs. During that time, these were small meetings by invitation only—about fifty of the cream of the crop of breast cancer investigators. During that time, we generated an incredible number of collaborations and joint projects and research areas that are still producing incredible consequences.

Tacey Ann Rosolowski, PhD:

Can I ask you just—is it accepted now in the field that breast cancer is more than one disease?

Gabriel Hortobagyi, MD:

Yes. Absolutely.

Tacey Ann Rosolowski, PhD:

Okay. You had said when you first began to talk like this people looked like deer in the headlights or something. I’m wondering what was that process and how long did it take?

Gabriel Hortobagyi, MD:

The process of repetition, the process of generating more and more evidence in support of that. By now the evidence is just overwhelming for that. It’s not unique to breast cancer because it’s like—it’s certainly—the lymphomas and leukemias preceded the solid tumors impact, and we’ve known for probably a good fifteen, twenty years—perhaps longer—that even the acute leukemias come in different flavors and types. Chronic leukemia is the same, and the lymphomas by now—I’ve lost track of how many different types of lymphomas there are.

Tacey Ann Rosolowski, PhD:

Uh-hunh (affirmative)

Gabriel Hortobagyi, MD:

Breast cancer was sort of one of the first solid tumors—if not the first—where this eventually took place. But it’s happening in lung cancer. It’s happening in sarcomas. It’s happening in colon cancer. It’s going to happen in prostate cancer. It’s going to happen in every single one of our malignancies when sufficient amount of research is done—

Tacey Ann Rosolowski, PhD:

Uh-hunh (affirmative).

Gabriel Hortobagyi, MD:

—and when these differences become relevant. So these differences would not be terribly relevant in breast cancer if all we had was chemotherapy. All right? But since we have now treatments that are very specifically targeting a subtype of breast cancer—they don’t work in other subtypes of breast cancer—these differences become highly relevant. Now that is starting to happen in other solid tumors.

Tacey Ann Rosolowski, PhD:

I interrupted you—I’m sorry—with my question. You were talking about how you were involved in creating the HER2 story—studies of Herceptin—

Gabriel Hortobagyi, MD:

Yes. So that has turned out to be a very exciting story because the HER2 positive breast cancer—the subtype used to be the worst prognostic subtype. Today it is starting to be one of the best. We have made an incredible amount of progress in a very short number of years with that. Simultaneously with that—and because some of the individuals involved in that little think tank I used to organize had other areas of investigation that were very exciting, and some of my own colleagues here in the institution were starting to look at other areas—I became involved in the development of other targeted therapies. But my role had changed because over the past let’s say fifteen years, increasingly as my department grew and as my research grew it was less and less about my own research and more and more facilitating and coordinating and sort of guiding the research of others. That is an interesting transformation because it’s frightening to some extent because you are departing from your own area of strength and moving into an area where you are much less comfortable.

Tacey Ann Rosolowski, PhD:

Uh-hunh (affirmative).

Gabriel Hortobagyi, MD:

Yet it has to happen because there is so much to do and so little time to do it that—unless you go through that transforming process—you end up becoming totally ineffective or you end up limiting yourself to just what you can accomplish yourself. Also, in the meantime, of course, I was taking other roles nationally. First I became much more involved with my specialty organization with ASCO and the AACR and eventually joined the board and became president of ASCO. Before that, I had become president of the International Society of Breast Diseases and was on the board of the International Association of Breast Cancer Research. Of course, that also takes time and effort away from your own research. You have to rearrange your resources and your activities. More recently, somewhere in 2005, I joined the Southwest Oncology Group and within a couple of years I became the chair of the breast committee. So that is a very large organization of about 2000 members. Now my role there is to coordinate the research of that large breast cancer group and to try to serve as the conduit, if you wish, for our own research here to be translated into national or international level research through SWOG—the Southwest Oncology Group. It’s an important role because there are some things that we can do very well here within the institution. Certainly most laboratory research can be done extremely well here. We have outstanding scientists and that’s great. We can do early clinical trials very well. In fact, at any one point in time we have 100 to 120 phase 1 or early clinical trials. But once you go much beyond that, the institution is too small, ironically, to do that. So for instance, now through SWOG, we are leading two clinical trials, one that requires 9400 patients and one that requires 4500 patients. Even though we are a very large group and we see about 3000 new breast cancer patients per year, when you really have to identify a small and homogenous subgroup of those, it would take us several decades to collect that number of volunteers to contribute to those clinical trials. Through SWOG, we are recruiting about fifty patients per week for each of these clinical trials. So in a question of about three years, we are going to finish the recruitment. That would not be possible without such an organization. You have to give up something in order to get something else. Being part of SWOG and working very closely with the NCI has also given me the opportunity to get some of my younger faculty members involved in getting the positions of leadership within national and international trials that will advance their careers and that will serve us. SWOG serves as an amplifier, if you wish, to our own research.

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