Targeted Therapies in Breast Cancer Webcast October 24, 2007 Julie Gralow, M.D. Hosted By Andrew Schorr

Transcription

1 Targeted Therapies in Breast Cancer Webcast October 24, 2007 Julie Gralow, M.D. Hosted By Andrew Schorr Please remember the opinions expressed on Patient Power are not necessarily the views of Seattle Cancer Care Alliance, its medical staff or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. Hello, this is Andrew Schorr. Welcome to another edition of Patient Power sponsored by the Seattle Cancer Care Alliance. We are delving into the subject of breast cancer. We've already talked about breast cancer screening and the latest information on who should be screened and how to catch breast cancer early to allay your fears if you've been worried about it and help you have a long, healthy life, but some people are diagnosed with breast cancer, and when they are, fortunately, therapies have been changing. They've been improving and still giving people the chance for a long, long life. Let's meet Dr. Julie Gralow from the Seattle Cancer Care Alliance. She is also the associate head of the breast cancer program at the Fred Hutchinson Cancer Research Center, and she is an associate professor of medical oncology at the University of Washington. Dr. Gralow is a noted breast cancer researcher and expert. Welcome back to Patient Power, Dr. Gralow. Well, thanks for having me again Andrew. Dr. Gralow, we want to talk about targeted therapies for breast cancer because certainly targeted therapies give us the sense that we can zero in and kill the cancer cells we're trying to get rid of and spare healthy cells and often limit side effects, which nobody wants. Where are we now with targeted therapies and how have they developed? INTRODUCTION It's a really exciting time in the treatment of breast cancer specifically and in cancer in general. We've really entered what we're calling the molecular or genomic era. We are understanding that not all breast cancer is the same, which makes sense but up until recently we've kind of been treating it as if it's all the same. Now we're understanding that dozens of genes and proteins are turned on and turned off in an individual cancer, and it's different across different breast cancers, and that's the SCCA101207/1003/AS/jf

2 information we're going to use to pick out which tumors are more likely to recur or not, which ones will respond to certain types of therapy or not. Now, it used to be that a woman was told, I'm sorry, you have breast cancer, and the cancer cells have grouped, and it's this large or it's spread to this lymph node or these other places, and they were sort of staged by that, but we didn't used to talk that much about the biology of the actual cancer cells. Now we do. Help us understand these different types and how that's leading to understanding of ways to zero in on the exact breast cancer biology you have. Right. The biology has really come to the forefront and might trump the old conventional staging related to the size of the tumor and the number of lymph nodes that might be involved with cancer. So, in early stage breast cancer, we now have an assay available that can look at 21 genes at one time, and it will group tumors into low-risk, intermediate-risk, high risk of recurrence based on the expression of multiple genes. It's an assay that can be done on a little tiny biopsy that's been fixed in formalin, and that information is now commonly used in very early stage patients where we're not sure whether chemotherapy will add benefit or whether it will cause more harm, and so that type of assay, a genomic profiling assay, is already being used in some early stage breast cancer patients to make determinations about what your recurrence risk is and whether you'll benefit from chemotherapy or not. Let me make sure I understand that. So, at the Seattle Cancer Care Alliance then often women are tested, and with this simple test you're talking about you say do we go down this course for treatment or do we go that way based on knowing the biology of your tumor and whether different treatments would work and be effective for you? Right. So, some of these proteins that we've known about for a little while include the estrogen receptor. We have some therapies that target the estrogen receptor and can shut it down, and HER2, the human epidermal growth factor receptor, and we also have therapies that target that protein. But that's really two proteins, and that doesn't tell the whole story, so now we're learning that if we look at a couple dozen, or we have some studies even looking at a 70-gene assay, that we can do even better. ESTROGEN ROLE IN THERAPY 2

3 Okay, so, help us understand now estrogen is most commonly involved in women's tumors. Where does estrogen come in, and how is that either a target or helps you decide on therapy related to that? Right, so the estrogen receptor is expressed in about 75-80% of breast cancers, and a normal breast has estrogen receptor. When we're premenopausal each month our estrogen and progesterone levels go up, and as we go through our menstrual cycle our breasts can get a little tender. We can actually feel the effects of estrogen and progesterone on our normal breast ducts that they make your breasts swell a little and a little bit tender and then as long as you don't get pregnant during that cycle it all goes back down again until the next month, and so we know that estrogen is a stimulus for normal breast cells, and in about 75-80% of breast cancers the cancer retains that estrogen sensitivity with the estrogen receptor. The estrogen receptor was really the first target for therapy in breast cancer, but we didn't know what the estrogen receptor was when we first doing trials where we manipulated the ovaries in young woman who were still premenopausal who had breast cancer, and we saw responses. We didn't understand why shutting down our ovaries and decreasing our estrogen production would work. We then had a drug that became developed, tamoxifen, which is a very effective drug still. It's been around for decades now. When we first discovered it, we really didn't understand really why it was working, and since then we've learned about the estrogen receptor that tamoxifen and its relatives, that have now been developed, target, and this is a class of drugs, antiestrogens in general, that are quite effective in treating a subset of breast cancer, not all breast cancer. So in a sense the estrogen receptor was the first target for therapies, but we didn't know what we were targeting at the time, so now we understand the target better, and we can design better drugs to that target. Okay, let's get into some of the targets and things that people hear about in the news. First of all, one subset of breast cancer is known as HER2/neu positive breast cancer. What does that mean, and where would we target therapies for that? GROWTH FACTORS About 20% of breast cancers diagnosed in the United States express HER2. That's a protein that is a growth factor, and when the tumor expresses it, it causes increased cell growth and division and spread, metastases. It's associated with a more aggressive type of cancer. Again, this is only about a fifth of all breast 3

4 cancers, and when this is expressed, we, in early stage, used to see worse survival. We did begin to understand this receptor in the early 1990s, and so some very smart people started deciding that we could design antibodies for example or other therapies that could shut down this receptor. In the laboratory some of these therapies looked very successful. So they would take HER2 positive breast cancer cells and use anti-her2 directed therapy, and the cells would stop growing, and they would actually die off, and so that led to studies in patients. Then the first HER2 targeted therapy that was approved was trastuzumab or Herceptin, that was approved in the mid-to-late 1990s for metastatic breast cancer and just within the last 2 years for use in early stage breast cancer, and it is a tremendous advance, but it's only effective in about 20% of patients; that's where understanding what's unique about each cancer is really important. Very effective therapy in early stage breast cancer, Herceptin has reduced recurrences by about half and deaths by about a third, and it's a pretty nontoxic treatment compared to chemotherapy for example. We are generally giving it with chemo because we see synergy, but the additional side effects from adding the Herceptin to standard, for example, Taxol chemotherapy are really minimal; a little bit of increase in heart toxicity that we monitor for and we watch carefully for but no nausea, no hair loss, etc. Where are we with sort of next generation drugs in this area? TARGETED THERAPIES Well just this year we've have had the approval of the 2nd HER2 targeted therapy, that's lapatinib or Tykerb. It also targets that same growth factor receptor, HER2, but it works inside the cell in an enzyme pathway as opposed to Herceptin, which binds to the outside of the cell to this molecule. So, it's possible that lapatinib or Tykerb is going to be effective in combination with Herceptin. It's certainly been proven, and it's now approved for use in tumors that have already been exposed to Herceptin and have been growing through it. That's where we're using it right now, but we're doing studies looking at adding the two together. We know they act at very different places on this molecule, and they may combine to be a better therapy. So, we're studying lapatinib or Tykerb, which is a pill. It's oral as opposed to Herceptin, which is intravenous. We're studying it in early-stage breast cancer now. So, it's very exciting. We have two HER2 targeted therapies with several coming down the line. One of my favorite ideas, and it's looking very promising in incredibly early studies, but this is not approved, is that there is now a conjugate with Herceptin, a proven therapy and a chemo agent, a chemo agent that was very toxic when we tried to 4

5 give it by itself, so it didn't get approved. It didn't progress because it caused too many side effects in patients, but when it's linked to the Herceptin antibody, it gets taken straight to the tumor cell that expresses HER2 so the chemo really does not get exposed to the rest of the body. Most of it goes directly to the tumor cell, and this is looking incredibly promising. So, by taking chemo, tagging it to a HER2 antibody and delivering it directly to the tumor, we can get greater tumor cell kill with little side effects to the normal tissue. It's a really exciting concept. We'll talk about participating in clinical research in just a minute. Now, beyond HER2 positive women, if you will, with that tumor type, are there other strategies that are being used more broadly in breast cancer? For instance, I've read about trying to limit the blood supply to the breast cancer and drugs that do that. Where do they come in and what are they? Some of our targeted therapies directly target the tumor cells, like HER2 target therapies, and then there is another category of target therapies that are targeting the tumor's environment and disrupting the ability of the cancer cell to be able to survive, for example, in the bone or the liver or the lung. So, the therapies that you're talking about are called anti-angiogenic therapies. Angiogenesis is the birth of blood vessels, and what tumors do to survive when they go and travel around and try to establish themselves in the liver or the lungs or the bones is they need to bring in a blood supply. They need to bring in nutrients. They need to bring in oxygen and sugar and proteins so that the tumor cells can grow. So, they send out signals to their environment that are telling the blood vessels to grow, and one very important blood cell growth factor that the tumor cells secrete is call VEGF and by understanding this process, researchers started developing drugs that blocked VEGF, which tumor cells secrete, and the VEGF receptor, which is found on blood vessels. We have several drugs that target VEGF that are approved. The one that has the most data in breast cancer is bevacizumab or Avastin, and it is an antibody that binds up all of the VEGF that the tumor cell is secreting. Right now it is approved in colon cancer and lung cancer, but we have a very powerful study in breast cancer that will soon be published, and it's sitting in front of the Food and Drug Administration, so we expect approval of this in breast cancer in the near future, but we're able to use it now because we have very strong data and it's approved for other reasons. There are a couple of other oral agents that target VEGF that are approved, for example, in kidney cancer and in liver cancer Sutent and Nexavar, and these are drugs that we're starting to study in breast cancer as well that target the blood vessels. This therapy, when added again to a little bit of chemotherapy, can double in the advanced stage setting the amount of time that the tumor will go without 5

6 progressing, and we call that progression-free survival. It's an important end-point in our trials of advanced breast cancer, and in the trial that will lead to the approval of Avastin in breast cancer it doubled the amount of time that patients went without their disease progressing from 6 months to 12 months, which that's an average. Some patients did better and some patients didn't do as well, but that's a very powerful difference, and it means that we have a good class of drugs that we need to learn how to better use and exploit. Dr. Gralow, we got in some questions after we did our program on breast cancer screening with Dr. Connie Lehman, and here are a couple I wanted to address to you. One is from Nazinga, if I got it right, and it actually came from San Antonio, Texas, and she asks; Avastin has been described as a targeted drug. Does that mean fewer side effects? Absolutely it means fewer side effects, but there are some side effects still. This drug impacts blood vessels, and we understand that VEGF, which is what Avastin targets, is not just one molecule. There are actually several versions of VEGF and several versions of its receptor, and some versions of it are more common in our normal tissues. So, for example, you really don't want to shut down all blood vessel growth in your body. If you got hurt and you had wound repair, you'd need to bring in new blood vessels. If, for example, you were having a heart attack or a pre-heart attack, your body's natural defence would be to bring in new blood vessels to try to bypass the blockage in your heart, so it's key that you don't want to shut down all the normal blood vessels while you want to shut down as much of the tumor's blood vessels as possible, so there are some side effects related to a little bit of an increase in bleeding and blood clotting because those are things that have to do with impacting our vasculature. High blood pressure is an interesting side effect of this class of drugs and headache was actually one of the most common symptoms when we tried to push the dose up to high levels, so there are some side effects, but they're not the traditional chemotherapy side effects. We don't really see nausea for example or hair loss or low blood counts. Okay. Dr. Gralow, here's another questions. This one is from Gloria in Brigham, Utah. She says, when is a therapy combining Herceptin and aromatase inhibitor indicated? And maybe you can help us understand what an aromatase inhibitor is. Right. So, this particular situation would pertain to a breast cancer that is positive for both HER2 because that's where Herceptin would be indicated as well as estrogen receptor because that's where antiestrogen therapies would be indicated such as aromatase inhibitors. They are powerful estrogen production inhibitors that 6

7 they work only in the postmenopausal setting, but they are really targeting estrogen receptor. So, maybe about 10% of breast cancer is positive for both the estrogen receptor and HER2. That's what this question is about. I told you earlier that we're generally when we give Herceptin, combining it with chemotherapy. A recent trial that was just presented within the last year looked at one of these aromatase inhibitors that target estrogen and plus or minus Herceptin at the time of a first recurrence in the metastatic setting, and it showed that the two together did better in terms of response and how long the tumor went before it started growing again compared to just the aromatase inhibitor alone. So, this gave us information we needed for me to answer this questions and to help our patients, which is a minority of patients, but those whose tumor expresses both HER2 and ER, estrogen receptor, and we're now starting to design trials where we might in HER2 positive patients who have early stage disease, non metastatic disease, maybe we can omit the chemotherapy if we give one of these aromatase inhibitors with Herceptin, and that's under investigation. In the metastatic setting, I think based on this trial that we had presented in the last year, we're quite comfortable using that combination and not mandating that Herceptin must be given with chemo at least in advanced breast cancer. THE BENEFIT OF CLINICAL TRIALS Dr. Gralow, one of the studies that came out was widely reported just recently talked about Taxol and questioning who was it effective for and maybe it was misinterpreted, but a lot of women have received Taxol and so they're wondering, well, was that effective for me or if I'm diagnosed with breast cancer should Taxol be part of my therapy? Help us understand what was published and what it means. So, the trial that created all this controversy just within the month of October was a trial of standard Adriamycin and Cytoxan chemotherapy with or without adding Taxol. It was started in about 1993, and we'd already seen a publication of the results, which showed that for lymph node positive patients in general there was a benefit to adding Taxol to standard A/C chemotherapy. So, this New England Journal paper that was recently published went back and they had the tumor blocks from about half the patients in the study, and they stained them for estrogen receptor and HER2, and what they reported was that for the patients who were about 50% of the patients in the study whose tumors expressed estrogen receptor but didn't express HER2, there didn't seem to be any benefit for adding Taxol, and what the press picked up, because that was the title of the paper, was that there's no benefit to adding Taxol if your tumor is HER2 negative. What the paper actually showed was that if the tumor was estrogen receptor negative and HER2 negative, there was benefit. So first of all there was benefit 7

8 even in some HER2 negative patients but my take-home message from this, and this was not meant to be practice changing or definitive, it was meant to be what we call hypothesis generating so that we design the next trial to definitively understand it; my take-home point is, it's clear that there are cancers that don't get a lot of benefit from chemotherapy in general. HER2 and estrogen receptor have nothing to do with how Taxol works, so I would question whether those 50% of patients who did not seem to respond to Taxol actually even benefited at all from the A/C chemotherapy. This group of patients, the estrogen receptor positive/her2 negative patients in general have terrific responses to antiestrogen therapy, and that might be a group that we should look in detail at omitting chemotherapy in and maximizing antiestrogen therapy maybe using very extended length instead of just five years of tamoxifen or one of these aromatase inhibitors, we're looking at 10 years and maybe not just one drug but sequencing; some of one kind of antiestrogen and some of another. I think this is an important study, and it really means that we need to be careful about giving chemotherapy to patients that are not likely to benefit, but it doesn t mean that we've figured out exactly what group we can safely omit chemotherapy in just based on this one study. Right. But fortunately research goes on. So tell us a little bit about where research is because for someone diagnosed with breast cancer today, and they here this term "targeted therapies" and they want to have the latest understanding of it applied to their exact tumor type or give them the best bet and that sometimes is in clinical trials. So where does that come in at the Seattle Cancer Care Alliance, and what's the work you're doing? Well, we have a great commitment to clinical trials and cancer because that is the only way that we can get new drugs approved, get new regimens, even using old drugs but in different combination tested, and so we have a tremendous commitment. We're an academic center that is committed to patient care as well as education and research and clinical trials. We have clinical trials that are going on around the country and clinical trials that are going on locally that are looking at all stages of breast cancer, some with some of these exciting new targeted agents, some looking at different ways of giving chemo. For example, in early stage breast cancer, we have a trial that's looking at giving the standard A/C somewhat differently with lower doses but more frequently. We're looking to see if that's more effective than big doses less often and also maybe less toxic, and in addition, in this early stage trial that we have going on, we're looking at a new form of Taxol. It's a form that has albumin, a protein, around it that makes it a bit of a different drug. It looks very exciting in metastatic disease, and again, we're taking it and giving low doses more frequently instead of high bolus doses both to see if that improves the effectiveness of decreasing recurrences as well as minimizing toxicity. So that's one 8

9 example of a trial in early stage breast cancer that's really come out of our own institution and is ongoing, and if this looks successful, we'll test it nationally. My own research is focused in large part on bone metastases and not only treating patients with bone metastases but preventing them in the first place. Just like we talked about how the tumor when it tries to spread wakes up its environment and stimulates its environment with the blood vessel targeted VEGF so when the tumor cell goes into the liver or the lungs it needs blood vessels brought in. When it goes into the bone, which is a common place for breast cancer to try to spread to, it wakes up the bone cells in a sense, and it says chew up some space for me, and as the bone is chewed up it sends signals back to the breast cancer that help it grow and divide and establish itself. Well, we'd like to prevent that. We'd like to block that. So I'm leading a big 4,500 patient national study right now looking at using drugs that are used for osteoporosis so they prevent bone breakdown, but we're using them in different doses, higher doses, at the time of a breast cancer patient's first diagnosis when we thing that there may be a few cells hidden in the bone trying to establish themselves but we don't yet see any bone metastases. So, we're studying whether giving these drugs, high doses of osteoporosis drugs, early can prevent the tumor from rooting itself down and therefore prevent it from showing up at a later time point. WHERE ARE WE HEADED AND CAN WE BE OPTIMISTIC? Well, it's fascinating and of course I know all of us support you in your work in helping gain greater knowledge to help people affected by this whether it's early breast cancer, hoping to avoid a recurrence, or if the breast cancer has spread. Dr. Gralow, one last question for you is, we talked about targeted therapies. That's our theme, and there's a lot of work going on. Are you optimistic that more are coming down the pike so that each individual person with their biology can ultimately more often have a therapy that's just right for them? Well that's absolutely where we're going. We are going to in the future take each cancer and test it for dozens of genes and understand what therapies will work and what ones won't work. We have hundreds if not maybe on the order of 1000 different drugs in various phases of development targeting many of these different receptors and proteins and genes that allow a cancer to be a cancer, and it's a very exciting era. It's changing right in front of our eyes. You know, I started practicing in breast cancer before we had HER2 targeted therapies, and that was really an aggressive form of breast cancer. Now I have patients who are living out, even with metastatic disease on Herceptin, they're living out normal life spans. So, we're going to be able to exploit that knowledge. HER2 and estrogen receptor and VEGF 9

10 are three targets we talked about, but we're going to have many others in the very near future, and we're going to be able to apply them only to a very select subset of patients and get the absolute best results for our patients. That's very encouraging news, and as always, we know though that early detection would be best of all, and so I did want to mention that the Seattle Cancer Care Alliance will be encouraging women to access the latest technologies in mammography with their "mammovan" in the ongoing fight against breast cancer, and the purpose of the mobile mammography van is to reverse the downward trend of women who get annual breast examinations since women in Washington have higher breast cancer rates than most other parts of the country, and we're going to look into that at another time too. You can find out about when the van will be in your area and make an appointment by calling this number: , or visit sccamammography.org. By the way, our next broadcast on Patient Power will be November 14th, and we'll be discussing Breakthroughs in Neuro-oncology with Dr. Marc Chamberlain. Dr. Julie Gralow, breast medical oncologist, thanks so much for being with us on Patient Power helping us understand targeted therapies for breast cancer, where we're headed, and also putting the news we hear sometimes about breast cancer therapy in perspective. Thanks Andrew. Thank you so much. I'm Andrew Schorr. You've been listening to Patient Power brought to you by the Seattle Cancer Care Alliance. Please remember the opinions expressed on Patient Power are not necessarily the views of Seattle Cancer Care Alliance, its medical staff or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. 10