INTERVIEW WITH DR. EDITH PEREZ
CHEMO FOUNDATION MEETING
NEW YORK, 2001

In the area of chemotherapy, we have been concentrating non-anthracycline regimens for patients with advanced disease, because we understand that a majority of patients receive anthracyclines in the adjuvant setting. So, at disease relapse we want to have options available for those patients. We started this process back in 1995 with our studies of paclitaxel and carboplatin as alternatives to anthracyclines, and that has evolved to a series of other trials. We're still very interested in the taxanes for the management of patients with advanced breast cancer, and we have two major trials at this time addressing those issues. One is a trial evaluating docetaxel in combination with carboplatin as first-line chemotherapy for metastatic breast cancer, and it makes a lot of sense for us at NCCTG to perform this trial, as we performed the original paclitaxel and carboplatin here in the United States. In addition to the docetaxel and carboplatin study, there is a second trial we have for first-line patients, but this time concentrating on those with HER2-positive breast cancer. In that setting, we are evaluating two different schedules of paclitaxel and carboplatin in combination with trastuzumab, either weekly or once every three weeks.

DR. LOVE: Can talk about what you're investigating right now in clinical trials?

DR. PEREZ: In the area of chemotherapy, we have been concentrating non-anthracycline regimens for patients with advanced disease, because we understand that a majority of patients receive anthracyclines in the adjuvant setting. So, at disease relapse we want to have options available for those patients. We started this process back in 1995 with our studies of paclitaxel and carboplatin as alternatives to anthracyclines, and that has evolved to a series of other trials. We're still very interested in the taxanes for the management of patients with advanced breast cancer, and we have two major trials at this time addressing those issues. One is a trial evaluating docetaxel in combination with carboplatin as first-line chemotherapy for metastatic breast cancer, and it makes a lot of sense for us at NCCTG to perform this trial, as we performed the original paclitaxel and carboplatin here in the United States. In addition to the docetaxel and carboplatin study, there is a second trial we have for first-line patients, but this time concentrating on those with HER2-positive breast cancer. In that setting, we are evaluating two different schedules of paclitaxel and carboplatin in combination with trastuzumab, either weekly or once every three weeks.

DR. LOVE: Can you talk about the docetaxel-carboplatin trial?

DR. PEREZ: It's a Phase II clinical trial. We felt that our original study of paclitaxel and carboplatin really demonstrated very good activity in terms of response rate and median time to progression and one- and two-year survival. We felt it was logical to evaluate the other taxane, docetaxel.

DR. LOVE: Right now, how do you see these two taxanes in terms of efficacy and side effects, in general, in the metastatic setting?

DR. PEREZ: Well, both the data and our clinical experience demonstrate that both taxanes are active drugs for the management of breast cancer. They're slightly different in terms of their tolerability profiles. So, there's some situations in which it may be more advantageous to use one versus another, but they're both very active agents.

DR. LOVE: Any thoughts in terms of whether one's more active than the other?

DR. PEREZ: No. We do not have any data to say whether one is absolutely better than another is, because right now my studies have not been published. However, this is being addressed as part of the ECOG-1199 adjuvant study that is being conducted through the breast Intergroup, and that will help us answer that question, at least in the adjuvant setting.

DR. LOVE: When you have a patient with metastatic breast cancer off protocol, how do you decide between those two agents.

DR. PEREZ: Well, you uttered the critical phrase there, "off protocol." I really try to discuss and enroll patients in clinical trials, if at all possible. And that's why we have so many clinical trials available. But, off protocol, we actually use them intermittently, depending sometimes on what has been used in the adjuvant setting, because that also is critical for our decision-making.

DR. LOVE: So, if you have, for an example, a patient who's gotten paclitaxel in the adjuvant setting, will you tend to use docetaxel in the metastatic setting?

DR. PEREZ: Correct.

DR. LOVE: Talk a little bit about what the potential synergies are between the taxane and carboplatin, both in terms of side effects and anti-tumor effects?

DR. PEREZ: Carboplatin's main toxicity in the past really was associated with the lack of understanding of how to appropriately administer the drug based on creatin clearance. So, we have learned over the last few years how to appropriately administer this drug. But still, the main toxicity remains thrombocytopenia, which is not one of the main toxicities of the taxanes. So, it's fairly easy to combine the taxanes with carboplatin, because the main toxicity of the taxanes is really related to myelosuppression in terms of neutrophils, but not thrombocytopenia.

DR. LOVE: Again, I understand your thought in terms of trying to get patients on protocols, but in a non-protocol setting for metastatic disease, do you tend to use combination therapy, or are you using single agents?

DR. PEREZ: I usually tend to use combination therapy, but I understand there is quite a bit of controversy regarding what the right approach is. In my opinion, there are a few clinical trials that have been performed addressing this issue, but we need more studies to really definitely answer the question. And the answer to the question may be different depending what agents are utilized. Many people have quoted the ECOG-1193 trial led by George Sledge - which we actually participated in as members of the Intergroup - which showed that for the AT regimen versus A followed by T, or T followed by A, there was really an improvement in response rate and time to progression for the patients who received combination therapy. And there was not a diminution in quality of life compared to single-agent therapy. Obviously, the answer would be clearer if there had been also a survival advantage, but that was not seen. So, for the majority of patients I tend to use combination therapy, because it is important, at least in my opinion, for quality of life, if I can tell the patient that the tumor has shrunk more than 50 percent. And if I can not only improve the response rate, but also improve the time to progression, that might be very worthwhile for that particular patient in front of us.

DR. LOVE: That's very interesting. It's so fascinating to talk to research leaders, because most of the time people cite that trial as why they don't use combination therapy.

DR. PEREZ: Well, you know, that study did not show that combination therapy was bad at all.

DR. LOVE: That's true, but they focus on the lack of survival benefit, and yet I see from your point of view the greater likelihood of chance for response.

DR. PEREZ: Correct. And we can then start thinking of other trials. One of them is the original pivotal trial of trastuzumab in combination with chemotherapy. As you know, in that trial the patients received concurrent chemotherapy and trastuzumab or they could receive chemotherapy followed by trastuzumab. And there was a clear survival advantage for the concurrent therapy compared to sequential therapy.

DR. LOVE: I think, though, that somehow, because that's Herceptin, people think of that separately. I want to talk to you about that. But first I want to clarify more about this issue, let's say, in the HER2-negative patient. For example, a typical scenario I'm sure you see a lot is a patient who's had an adjuvant anthracycline-containing regimen and now has metastatic disease. So, what combination would you use in that situation, or how do you sort of sift through using chemotherapy in a patient who's relapsed relatively recently after receiving anthracycline adjuvant therapy?

DR. PEREZ: That is a very challenging question, and at the same time, one we have to face practically on a daily basis. And the challenge comes from the availability of a lot of different regimens, which appear to give fairly similar benefits to our patients, but we do not have definite clinical trials in terms of phase III studies saying that one is absolutely better than another.

DR. LOVE: So, what do you do?

DR. PEREZ: I tend to use paclitaxel and carboplatin, because we have the most data with that regimen, as we tested it in our trial. We are starting to use docetaxel and carboplatin. We are starting to use combinations with gemcitabine, because that agent also has activity in the management of advanced breast cancer. We at NCCTG have just started a study of oral vinorelbine.

DR. LOVE: Wow! Oral vinorelbine? I didn't even know it could be given orally.

DR. PEREZ: It's fairly new information.

DR. LOVE: So, is it absorbed predictably?

DR. PEREZ: Yeah. It's well absorbed, and some initial studies have been performed in Europe, and it may be that you will see that the oral regimen will be much more convenient for patients. If we can demonstrate significant response and tolerability, then it will be very easy to combine this oral vinorelbine with other agents. So, we're trying to switch our approach to metastatic breast cancer, using regimens that potentially have good activity and better tolerability than what we've had in the past.

DR. LOVE: That's interesting. Why wasn't it developed as an oral agent, if it's absorbed well?

DR. PEREZ: I think it's a fairly new development. I think the company has had plans for the development of this drug for a long time - as many other companies have - in terms of their individual agents.

DR. LOVE: Interesting. You know, one trial that did come out recently with a survival advantage was the Taxotere-capecitabine study. What did you think about that study and do you ever use that combination?

DR. PEREZ: Yes. The results of the Taxotere-capecitabine study came as a surprise to some, but really not to others. And the reason it may have come as a surprise to some is that that study showed that the concurrent use of Taxotere and capecitabine was better than using the single-agent Taxotere. That trial has been criticized by some, because not every patient who received Taxotere then went on to receive second-line capecitabine. So, for the purist trying to answer the question of sequential versus concurrent therapy, this trial doesn't give us the exact answer. But it is dramatic that there was a survival advantage, and we have to take it very seriously. One of the challenges, though, for that particular regimen was the high incidence of hand-foot syndrome, based on the doses of chemotherapy utilized. So, this is something we take into consideration and, when we use that regimen, we usually lower the dose of capecitabine, because we must try to ameliorate this side effect of hand-foot syndrome.

DR. LOVE: What's been your experience with that combination?

DR. PEREZ: It definitely has activity.

DR. LOVE: And, again, when you sort through the options with, again, a patient who's had adjuvant anthracycline, is that one of the regimens that you usually consider or that you use?

DR. PEREZ: Yes, it is one of the regimens, and it's not only my opinion. This combination has been approved by the FDA, so I think the data justified utilization.

DR. LOVE: What are some of the factors you consider in selecting one of these combinations?

DR. PEREZ: Number one is patient performance status. Number two is end organ function, because some patients may have poor liver function, poor renal function, and those things play a role. The third one is patient convenience. Some patients actually want to come to the clinic on a weekly basis, because they want to be evaluated and be in contact with their medical personnel. Other patients may live far away and they don't want to come to the clinic once per week. So, for them we tend to use a once-every-three-week regimen.

DR. LOVE: You talked about the issue of developing oral chemotherapeutic regimens and gave the interesting example of vinorelbine, which I didn't even know about. The one agent that we have right now is capecitabine. What about single-agent capecitabine? Where does that enter into your practice?

DR. PEREZ: Until now, it has really been used after the taxanes and anthracyclines - again, following the FDA approval of these agents. We have also seen significant clinical activity with this agent, and the benefit of capecitabine - which is actually not only seen with capecitabine, but it's also being seen now with gemcitabine and with vinorelbine - is that they don't cause alopecia. That becomes an important issue for patients with advanced breast cancer. If they have not had alopecia before - but especially if they've had alopecia and their hair has grown and then they develop relapse - it is very important for us to think of regimens that will allow them to maintain their hair, because it's very important for the patients to have the appearance of being as normal as possible.

DR. LOVE: It seems like most people are using lower than the approved dose of 2500 milligrams of capecitabine. A lot of people start at two grams. Is that what you do?

DR. PEREZ: Yes. That's what we do, too. And I feel it is going to be important for an eventual formalization of what the right or appropriate dose of capecitabine should be for private oncologists. Not only for private oncologists but also academic oncologists.

DR. LOVE: What's been your experience when you use that dose and then dose-reduce for toxicity in terms of quality of life and side effects of the drug?

DR. PEREZ: The side effects of capecitabine are really minimal except for the hand-foot syndrome and the occasional myelosuppression and diarrhea that occurs. But I haven't seen too many of the two latter side effects. The main problem really has been hand-foot syndrome. If we use the 2,000 per meter squared for the 14 days, hand-foot syndrome can still occur, but it will be in less than 25 percent of the patients. And what I tend to do is then play around a little bit with the schedule and the dose, because there are no firm guidelines we can use. So, sometimes I drop the dose to 1,500 per meter squared for 14 days. Sometimes we've tried one week on and one week off. So, we try to find a regimen that allows the patient to have the best quality of life.

DR. LOVE: I'm not going to forget to circle back to the trials that you're involved with, but I know you're giving a talk this afternoon on breast cancer in the elderly. I don't know if you're going to be talking about it or not, but one of the things that usually comes up under that discussion is Hyman Muss' new adjuvant trial. Any thoughts about that?

DR. PEREZ: Yes. We at NCCTG will be joining Hy and the CALGB in that particular adjuvant study, and that is the study which will address patients older than 65, and the physicians will be allowed to recommend to the patient this therapy, which is based on either CMF or AC in one arm versus oral capecitabine. The patients eligible for that trial will be those with tumors greater than 3 centimeters.

DR. LOVE: Is that the only criteria, or are there other criteria besides that?

DR. PEREZ: There are some other criteria, as we usually tend to have in adjuvant studies. But those are the primary criteria.

DR. LOVE: Node negative or node positive?

DR. PEREZ: It's independent of node status.

DR. LOVE: What do you think about that study?

DR. PEREZ: I think it's a very good study, and we have been in discussions with Hy over the last few months as he was developing the trial, and we are very supportive of the idea of moving the adjuvant therapy area into a new direction of oral therapy.

DR. LOVE: Are you looking at it as mainly a way to give adjuvant therapy orally with maybe less toxicity, or do you have any hopes or thoughts that perhaps it might have greater efficacy?

DR. PEREZ: Well, I hope it has greater efficacy, but we'll have to move in both directions. We want greater efficacy and fewer toxicities for our patients. So, we'll take both if we can, but if only one of them is there, then that's going to be good.

DR. LOVE: Any other things that are going on in terms of trials in the elderly? It's amazing to me how few trials there are like this, looking at elderly women with breast cancer. Any others that you're aware of?

DR. PEREZ: Well, actually, the oral vinorelbine study we are doing at NCCTG is targeting women 65 years or older, too. It's going to be a Phase II clinical trial.

DR. LOVE: So, the dose and toxicity has already been established for that?

DR. PEREZ: Yes, and we actually have a plan for dose escalation. We're starting at a dose of 60 milligrams per meter squared once per week in a tablet, and then if there is no evidence of any significant toxicity in the first month, then we will dose escalate to 70 milligrams per meter squared per week.

DR. LOVE: Any other large Phase III randomized studies looking at elderly women? When Hy presented the issue of the elderly at the consensus conference - and I know you were there - it was interesting how little, other than his trial, was even being discussed.

DR. PEREZ: Yes, that's an area that really deserves a lot of attention and, at the same time, it is not that easy, because some people may say, "Well, why are you doing studies solely in women who are older than 65?" That would mean that you're actually discriminating or making them different than other women with breast cancer. And then the other side, we have the information from SWOG and other groups, saying that all the women are typically not enrolled in the regular clinical trials we write. So, what we essentially would need to do is increase awareness that women older than 65 can tolerate therapy as well as women younger than 65, that they can derive benefit from this treatment as long as their end organ function is good, and not exclude them from the major clinical trials.

DR. LOVE: One of the things that was really interesting about that SWOG study of elderly women was it looked like the older women were just as interested in participating.

DR. PEREZ: Correct, and in spite of that, Laura Hutchins - when she published this study in the New England Journal in 1999 - showed that although so-called elderly women comprise 49 percent of the breast cancer cases in the United States, there were only nine percent of older SWOG breast trials in terms of the percentage of participants who were older than 65.

DR. LOVE: Yeah. That was very striking. I want to get back to the trials that you're involved with, but one more question I have, though, is, what are some of the major themes or messages you are going to try to get across in your talk this afternoon?

DR. PEREZ: One of the major themes is that the decision for systemic therapy for older women should be based on the biology of the disease, the patient's performance status and end organ function, but not based solely on her age.

DR. LOVE: Interesting, when you look at geriatrics, sometimes you get the feeling we have this sort of arbitrary number of 65, and yet if you actually think about it and look at the physiology of aging, it seems like it ought to be more towards 75 or 80. I mean, there's not that much difference between a 65-70-year-old woman and a 50-year-old woman, physiologically, I don't think. What do you think?

DR. PEREZ: These are data I've been looking into over the last year or so, and the information is surprising, because 75 years does not mean that one will die the next year. Actually, about 25 percent of women who are 75 years of age are expected to live about 17 years.

DR. LOVE: And I think that the median life expectancy of a 65-year-old woman is about 20 years, isn't it?

DR. PEREZ: That is absolutely right, yes. So, life is not over at 65 for most, and certainly not over at 75, and even for people who are 80 years of age. Even when one thinks of the extreme age group of 90, in that group the life expectancy is about five years. So, we have to think of how to manage their medical problems the best we can with the current tools and not just give up on people just because of their age.

DR. LOVE: Let's get back to the trials that you're involved with. You mentioned your interest in the metastatic setting and the HER2-positive patients, what are the trials or trial that you have right now, looking at that?

DR. PEREZ: The main trial we have is one that is evaluating the optimal scheduling of chemotherapy with Herceptin, or trastuzumab. Typically, Herceptin has been used once per week, and new data became available earlier this year with a once-every-three-week regimen. So, we felt that this was ideal to test in combination with chemotherapy, because sometimes we give chemotherapy weekly, sometimes once every three weeks. So, that's why we have this particular clinical trial, which is NCCTG-983252, using both regimens, to see what we find in terms of tolerability and activity.

DR. LOVE: What is the randomization?

DR. PEREZ: It's paclitaxel, carboplatin and trastuzumab once every three weeks or paclitaxel, carboplatin and trastuzumab all given weekly.

DR. LOVE: Who's eligible for the study?

DR. PEREZ: Patients eligible to receive first-line chemotherapy for metastatic disease, and the tumor has to be HER2-positive, either via FISH for gene analysis or immunohistochemistry as 3+ when we're looking at HER2 protein.

DR. LOVE: I'm guessing that you're powering the study to look for equivalence in terms of benefit and maybe the difference in side effects and toxicity?

DR. PEREZ: Yes, we are performing the study as a randomized phase II trial, because performing a Phase III would really need too many patients. And we want just to get an idea of tolerability and activity.

DR. LOVE: That's interesting, because I always wondered what the term "randomized phase II trial" means. How do you define that?

DR. PEREZ: It's interesting, because a randomized phase II means that we're not technically comparing the results of one study versus another, but it gives us some idea of the value of one regimen versus another. But they're really treated independently. Sometimes we have similar backgrounds for a trial, and we're just trying to change one small thing or another, and in that case, it's ideal to perform a randomized phase II. Other people randomize phase II's to save time, because they may have three completely different regimens and they want to get an idea of what may be worthwhile to take to a phase III study.

DR. LOVE: That makes perfect sense. In other words, it's almost like two phase II studies that are being run at the same time and you're kind of randomizing because maybe you think you might get some hints?

DR. PEREZ: That is right, and usually you have similar eligibility criteria, so it makes it a lot simpler to write a study that may answer three questions than to write three independent studies.

DR. LOVE: In terms of side effects and quality of life in this study, obviously you're going to have the issue of inconvenience of the weekly versus q three weekly. What about in terms of what you are expecting in terms of side effects and toxicity?

DR. PEREZ: Well, you know, the issue of inconvenience of the weekly regimen is an interesting one that I would like to address. You may know that I performed a very large trial of weekly paclitaxel that is actually going to be published in JCO in November [2001]. And we ultimately enrolled 212 women. And when we started the trial, I thought it would be very difficult for patients to come on a weekly basis, and I was very surprised. The delivered dose intensity was 77 milligrams per meter squared per week. So, women did not mind coming to the clinic on a weekly basis. But, as a clinician investigator, I always try to do something better for our patients, and I think that's why it's also a good idea to look at other alternatives. But I don't think the weekly was that difficult. Actually, it was much less difficult than I had thought.

DR. LOVE: One of the things that people talk about is the bonding that occurs between the patients and the nursing staff and the office staff and the potential benefits. But still, coming in once a week for, you know, a longer period of time, you have to think is going to interrupt their quality of life.

DR. PEREZ: It may. In our trials, we have always included quality-of-life parameters, and I have been pleasantly surprised. Also what we have done in all of these trials is that although they were initially written once per week until progression or toxicity, we really allowed patients to take weeks off, depending on social reasons. Actually, in our trial, there was a number of 15 percent of dose reductions or interruptions, and half of them were exclusively for social reasons, because we understand people have lives. So, it's not that they have to come to the clinic on a weekly basis.

DR. LOVE: Can you summarize actually what's going to come out in that paper?

DR. PEREZ: The paper is going to demonstrate that paclitaxel, 80 milligrams per meter squared is feasible, tolerable and an active regimen for the management of patients with metastatic breast cancer. Specifically, breast cancer patients who are heavily pre-treated, because in that trial we allowed up to two prior chemotherapies for metastatic disease in addition to adjuvant therapy. We enrolled patients who had had taxanes once every three weeks, high-dose chemotherapy and transplantation. We allowed patients who had up to grade 1 peripheral neuropathy at study entry. And in spite of all this, paclitaxel, 80 per meter squared, was very good in terms of therapeutic ratio for the management of metastatic breast cancer.

DR. LOVE: What about the issue of cross-resistance between the two taxanes? The patient has progressed on one, in terms of receiving a second one.

DR. PEREZ: There are actually very little data to answer your question. I'm aware of one study in which patients received docetaxel after they had received paclitaxel, and the response rate was about 18 to 20 percent. So, there may not be complete cross-resistance between these agents.

DR. LOVE: You mentioned in the metastatic study the eligibility criteria in terms of IHC and FISH. Do you want to talk a little bit about that?

DR. PEREZ: We're actually submitting a paper to the Journal of the National Cancer Institute within the next week, in which we will be reporting the data of concordance of HER2 testing as part of our N-9831 adjuvant study. This is the trial, which is evaluating Herceptin, or trastuzumab, in combination with chemotherapy to determine whether this monoclonal antibody adds to the benefit of chemotherapy. When we wrote this trial, we included a plan for central analysis of HER2 in the first 100 patients or so, and we decided that we would change the protocol depending on our data, if necessary. Well, the study has now been completed, and the data we are submitting relates to the first 119 patients who were enrolled. And unfortunately, we found a high level of discordance in terms of HER2 testing by immunohistochemistry or even FISH in the community, compared to central testing.

DR. LOVE: This actually is an Intergroup study, correct?

DR. PEREZ: That is right. This is an Intergroup study begin led by us at NCCTG, but other members of the Intergroup, including CALGB, ECOG and SWOG are also contributing to this trial.

DR. LOVE: What's the total accrual that you're shooting for in the entire trial?

DR. PEREZ: Three thousand patients.

DR. LOVE: Okay. So, what did you find?

DR. PEREZ: We found that there is a significant problem with HER2 testing in the community. For our trial, or for this preliminary manuscript, there were only nine specimens that were sent in using FISH from the community, but we found discordant results in six of those.

DR. LOVE: Wow! So, these were FISH-positive?

DR. PEREZ: Those were FISH-positive in the community, and when we tested them centrally, we did not find that the test was truly FISH-positive. It is not good. We are trying to investigate that issue, because a consensus that had been developing was that if we used immunohistochemistry, it wasn't good. But our data are also a little bit of concern regarding FISH, although the numbers of patients is very, very small to date. So, I cannot conclude that FISH is a bad test to be performed in the community, but we need to look a little bit more into why there should be a discordance when FISH is done.

DR. LOVE: And these nine patients, were they also tested with immunohistochemistry?

DR. PEREZ: Yes.

DR. LOVE: What were they? IHC?

DR. PEREZ: Yes, in some of those cases, the IHC was positive, but not in all.

DR. LOVE: Now, what about the IHC concordance?

DR. PEREZ: Okay. It was about 75 percent, so that means that if the community laboratory tested the specimen as 3+, we only found 3+ centrally in 75 percent, so 25 percent of those were not positive centrally.

DR. LOVE: Were they 2+ or are they even lower than that?

DR. PEREZ: We had zeros, ones and twos.

DR. LOVE: Now, out of those 119 patients, how many were from the community and how many were from tertiary centers?

DR. PEREZ: The majority of those were from the community.

DR. LOVE: And what about the concordance in the tertiary centers for both FISH and IHC?

DR. PEREZ: In our first analysis, we couldn't establish any statistical difference between big laboratories and small laboratories, because we had 65 different laboratories for 119 specimens.

DR. LOVE: But you kind of focused your comments on community assays. Do you feel comfortable that, in a tertiary center, the assay is going to be more reliable?

DR. PEREZ: We don't know. We feel that it's logical that the more assays a laboratory performs, the better their performance, but this really has not been tested in any randomized fashion. But this is something that is of concern to us, and that's one of the reasons for us changing the eligibility for entry into our clinical trial.

DR. LOVE: Which is now what?

DR. PEREZ: We are going to require either central testing before the patient is enrolled in the study, but we are also going to allow another possibility, and it is that patients can still be enrolled based on community testing or we are requesting that the tumor specimen is submitted to us at Mayo for central testing within the first month. So, the patients can be started on their anthracycline/cyclophosphamide treatment, and we'll have time to figure out whether the tumor is indeed HER2-positive. If it's HER2-positive, then the patient continues on study. If it's HER2-negative, then the patient and the physician will be informed of this data, and then it will be up to the physician to make a decision regarding what adjuvant therapy that patient should receive.

DR. LOVE: If that patient in the central lab, in fact, is HER2-negative, will they be allowed in the trial?

DR. PEREZ: No. The patients will be registered into the trial, so we will continue following that patient, but the decision on adjuvant therapy will be left at the investigator's discretion.

DR. LOVE: This data obviously raises the concern of treating patients with Herceptin who, in fact, are HER2-negative, which has one implication: unnecessary treatment. But the flip side of the coin, which this data doesn't address at all is the question of if the assays are not being done correctly, could there also be patients who are being labeled as being HER2-negative in the community, who are actually HER2-positive?

DR. PEREZ: You're right. This is not something we're addressing in any of our trials, because all of our trials require HER2 positivity by community laboratories. We at Mayo actually have done another type of study, and there is a manuscript we have in press in Mayo Clinic Proceedings, in which we looked at HER2 testing, based on 1,500 specimens sent to Mayo medical laboratories over a five-month period. We took all the specimens labeled as 2+ - and there were a total of 213 specimens - and we tested them by HercepTest for protein or using the PATH Vision Visis kit for gene analysis. We found that only 12 percent of the tumors scored as 2+ by HercepTest actually had gene amplification by FISH.

DR. LOVE: I guess my question would be are there patients out there who are being labeled as HER2-negative who might be, for example, FISH positive?

DR. PEREZ: Oh, yes. And our feeling is that that number may be six percent, but more data are really required. We are actually going to do a prospective study, because we get so many specimens for testing at Mayo, in which we are going to be looking at zeros and ones to see if we can address this issue of how many of those are truly positive.

DR. LOVE: So, if I'm a community oncologist in the audience at a lecture that you're giving and I raise my hand and say, "What do I do about HER2 testing in my patients? I'm in a little community, a hospital out in the middle of wherever."

DR. PEREZ: I think medical oncologists should be involved with their pathologists to understand the experience their pathologists have in terms of doing testing by immunohistochemistry or FISH, because I don't think we should leave that only to the pathologist to give us a report. We should be involved, because we are treating the patients. And if the pathologist says, you know, "I've done only one immunohistochemistry," or "one FISH," perhaps the medical oncologist would want to send the specimens to a laboratory that does many more than one every week.

DR. LOVE: Do you think that all primary breast cancers or any other tissue removed from a breast cancer patient for a metastasis should be tested for HER2?

DR. PEREZ: Yes, that is our approach. That is part of the standard evaluation of all new invasive breast cancers diagnosed in Mayo Clinic in Jacksonville, because it helps in three ways. Number one, it may help us for determination of prognosis, especially in patients with node-positive breast cancer. Number two, it may give us an idea of the potential benefit of anthracyclines versus non-anthracyclines in the adjuvant setting. And number three, it identifies patients for clinical protocols, such as N-9831.

DR. LOVE: Do you have any idea right now what fraction of breast tumors are being tested for HER2 across the country?

DR. PEREZ: No, because at some institutions they only test patients who are node-positive. I think this is something that is changing nationwide, as education has improved and there is increased awareness of the potential value of HER2 testing in the determination, prognosis and decision for therapy.

DR. LOVE: You talked about the issue of HER2 as a negative prognostic factor in the primary breast cancer setting. Do you see HER2 as a separate kind of entity, and also what about in the metastatic setting?

DR. PEREZ: It appears that HER2 is associated with a worsened prognosis, but we still do not understand all of the pathways in which HER2 is of importance. So, it may be that there is a downstream molecule that we have not yet identified, which is the important molecule. So, that's why, if we think of HER2 testing and whether we should use immunohistochemistry and FISH, I remain actually quite open to the idea that this may not even be the best test we will ultimately have to predict for benefit of Herceptin. It may be another molecule, and that's why I don't think we can be too dogmatic about this. Even in the retrospective studies performed - and the classic example was the one by Chuck Vogel in his very elegant study of single-agent Herceptin for patients receiving first-line therapy for metastatic breast cancer - it was demonstrated that by using FISH - again, in a retrospective fashion - only 40 percent of patients derived benefit in terms of response rate from Herceptin. So, there must be something else that may predict for a response to Herceptin, and it may be different than HER2 by FISH or immunohistochemistry.

DR. LOVE: Do you think, though, that HER2 is enough of a negative prognostic factor? For example, I've heard people say, "If I have a patient in the metastatic setting who was HER2 negative, who relapses shortly after chemotherapy and seems to have an aggressive course I might want to retest the patient or send the patient for FISH." Is it enough of a clinical entity that you approach it that way?

DR. PEREZ: Yes, I do. We have targeted therapy against HER2, and it is very important for us to explore the possibility that the patient may be able to benefit. If it takes doing one test by immunohistochemistry or FISH - in the big picture - a test may cost $200 or $400 versus the cost of therapy or the life of our patients.

DR. LOVE: One of the problems with FISH, of course, is that it's not done that much. It's a little bit more complicated. It's more expensive. Do you see that really, ideally, patients should just be FISH'd and, if we had the capabilities to do that, but just not do IHC?

DR. PEREZ: Well, actually, we addressed that in the manuscript that is going to come out in Mayo Clinic Proceedings, and we recommended an algorithm. The algorithm is to start with immunohistochemistry, because it's an easier test to do and it's less expensive, as you mentioned. If the tumor is zero, 1 or 3, stop there. If the tumor is 2+, definitely do a reflex FISH testing. And, at our facility, we don't even have to ask for a second request. The pathologists automatically perform the FISH analysis. But we think that perhaps it's not a good idea to do FISH for everybody, because the majority of patients will be negative, you know. FISH positivity accounts for only about 20 percent of patients with breast cancer, perhaps 20 to 25 percent. So, I'm wondering if we should test 100 percent to find 25 positive, or if we can use immunohistochemistry to guide us in terms of whether FISH should or should not be done. And that will save money and time.

DR. LOVE: Well, that does sound like a global socioeconomic, cost-effective approach, but on the other hand, we know - and I think Chuck Vogel did report in which, seven percent who were IHC 0, who were actually FISH positive?

DR. PEREZ: Correct. But his study was a very small study. The entire trial had a little more than 100 patients. So, the 95 percent confidence intervals were quite wide.

DR. LOVE: But we know from lots of different surveys of breast cancer patients how interested they are in every possible benefit. I think that if it were me or if a breast cancer patient was asked, "Listen I know there's only a seven-percent chance or a one-percent chance that, in fact, this test is going to be of use," on the other hand, here's an agent which can be helpful, doesn't have very much toxicity, I think most people would say, "Well, why not do the test?"

DR. PEREZ: You're right, and this is a fact that we should discuss with the patients on a one-to-one basis. I am completely in favor of that, and this is something I have done in clinical practice. Especially if a patient has a primary breast cancer five years ago and then the patient develops metastatic disease, I want to explore all the potential avenues for treatment for that patient, so I retest the tumor.

DR. LOVE: That brings up the question, too, of looking at tests that have been done more than a couple of years ago when we had the HercepTest. How do you approach that? Do you accept those results?

DR. PEREZ: In the majority of cases, we use the original tumor, but in many of the cases, we have started to re-biopsy patients, because there are not enough data telling us of the concordance of HER2 between a primary tumor and the metastatic tumor. And, again, we must explore all potential treatment options for our patients.

DR. LOVE: I want to talk a little bit about the adjuvant studies you're involved with, but one more follow-up question. You talked about the concordance issue and your study. How does that correlate with what the NSABP has seen in their adjuvant study? I know they had a similar sort of earlier analysis.

DR. PEREZ: One of the benefits of participating in the cooperative group mechanism is that we work very closely with each other, and actually both the NSABP and us are sending the manuscripts together to the JNCI.

DR. LOVE: And do you want to summarize what they found?

DR. PEREZ: Yes. Our data are very similar, and that's why we felt it was going to be important to work together on this. They are two independently run studies but running in parallel. We felt it was important to submit the manuscripts together to be able to deliver the message in a stronger fashion than two independent studies published in two different journals.

DR. LOVE: That's interesting. I'm a member of the NSABP, and I'd seen the fax that they had sent out, and, as you were saying, I was thinking it sounds like exactly the same story, although I don't remember - did they have people who were FISH-positive who, in the central lab, were FISH-negative?

DR. PEREZ: No. The data reported by the NSABP - and I can talk about this, because it was publicly disclosed at their meetings - do not include the analysis by FISH in the community and then central testing, whereas in our trial we included that. But, again, the number of patients enrolled based on FISH was very small in this first subsets of patients analyzed.

DR. LOVE: The other thing I remember about their data was that they found the same thing - people who are IHC 3+ in the community, then not being 3+ in the central lab. But they, at least, tried to break it down in terms of community lab versus tertiary lab, and it looked like maybe it was a little bit more reliable in the larger tertiary labs.

DR. PEREZ: Yes, that is correct. And, again, this information comes from the letter sent to everybody - not from this confidential manuscript - but yes, they were able to establish some relationships. But, again, the numbers are fairly small. So, we felt at NCCTG and the breast Intergroup that we just couldn't even make that kind of statement. But what they said makes sense.

DR. LOVE: Yes, it does. I wouldn't be surprised if it turns out to be exactly what you said, that whether it's community or tertiary, it's going to be a volume kind of issue. The more tests you do, the more likely it is to be reliable.

DR. PEREZ: I completely agree with that. So, it's not to say that we at Mayo or that we at big tertiary centers are better than the community pathologists, it's maybe just a matter of volume.

DR. LOVE: I wanted to go on to the adjuvant trials. Can you talk a little bit about the adjuvant trials you're involved with now?

DR. PEREZ: We, at NCCTG, are contributors to the overall effort by the breast Intergroup in the adjuvant trials. So, we have been participants in ECOG-1199. We will be participating in Hy Muss' study for women older than 65. We will be participating in a study that will be led by Larry Shulman, comparing AC versus one of the taxanes, which will be administered weekly. But the protocol we are the leaders of is N-9831, which is the adjuvant study for patients with node-positive, HER2-positive breast cancer. And this trial is based on solid scientific principles, and it will join the three other worldwide studies being conducted to help us answer the question of whether Herceptin acts to the benefit of chemotherapy in this group of women with poor prognoses following resection of breast cancer.

DR. LOVE: What are the criteria for entry and the randomization arms?

DR. PEREZ: The main criteria includes node positivity, either by sentinel node or full axillary dissection, HER2 positivity by immunohistochemistry 3+ or FISH, no previous cardiac dysfunction, and the ability of the patient to understand the protocol process and sign a consent form.

In terms of the randomization arms, we have three different arms in our trial. The first one is AC followed by weekly paclitaxel. The second arm is AC followed by weekly paclitaxel followed by trastuzumab for one year. And in the third arm, it's AC followed by weekly paclitaxel concurrent with trastuzumab and then trastuzumab for the rest of the year.

So, in the three arms of the study, the patients receive six months of chemotherapy, and we're actually asking another question of whether trastuzumab should be used sequential to chemotherapy or starting concurrent with the paclitaxel treatment.

DR. LOVE: Any reason why it wouldn't be used concurrently?

DR. PEREZ: One of the reasons for us having a third arm and a second arm in the study is the concern of potential cardiac toxicity when anthracyclines are used closely with trastuzumab, and we wanted to have an arm in which there was at least a three-month separation between those two agents and that arm, too, in which they get AC, then paclitaxel and then trastuzumab.

DR. LOVE: But even in the combination arm, they're actually not getting the AC and Herceptin at the same time. You don't start the Herceptin until the taxol starts?

DR. PEREZ: That is correct. In terms of this adjuvant study, we want to avoid using Herceptin in combination with the anthracyclines, because of the prior data from the pivotal trial.

DR. LOVE: Now, you talked before about the early analysis for concordance in terms of HER2 assays, and I know the NSABP is doing a similar study. Can you talk about what the difference is between their study and yours?

DR. PEREZ: The NSABP is also conducting a very good trial, based on solid scientific principles, but their study has two arms. This is NSABP B-31, and the eligibility criteria are very similar to ours, but the two arms are AC followed by paclitaxel versus AC followed by paclitaxel concurrent with trastuzumab for the three-month period, and then trastuzumab alone. So, NSABP is using paclitaxel once every three weeks, as it was done in CALGB 9344, but we are utilizing paclitaxel weekly.. Another difference between our trials is that NSABP starts tamoxifen, if tamoxifen is indicated, concurrent with AC, whereas in our Intergroup study, tamoxifen is started after the completion of the six months of chemotherapy.

Another potential difference relates to the schedule of trastuzumab. We are submitting an amendment to our protocol so that the trastuzumab can be administered once every three weeks, whereas NSABP will maintain the trastuzumab on a weekly basis for one year. This will make our study similar to two other trials. The HERA trial and BCIRG 006 are also using trastuzumab once every three weeks, but in the BCIRG trial the situation is a little bit more complex, because they're using trastuzumab weekly with the chemotherapy, and then after chemotherapy is completed, then trastuzumab is given once every three weeks.

Both of those trials are multinational studies - mainly in Europe with members from the EORTC and other cooperative groups in Europe - whereas B-31 and N-9831 are mainly U.S. studies with some Canadian sites. The HERA trial has not started yet, as far as I'm aware. And the BCIRG study is ongoing.

DR. LOVE: You talked before about the early analysis that was done both in the NSABP trial as well as your trial in terms of concordance for HER2 assays. I've heard that there's also going to be an early analysis looking at ejection fractions. Any data on that?

DR. PEREZ: Yes. Both the NSABP and our group with N9831 are paying particular attention to cardiac tolerability. At this time, there are no red flags that have been raised, and both studies continue accruing patients.

DR. LOVE: Can you talk about exactly what cardiac monitoring is being done in the studies and I assume the data monitoring committees are following this very closely.

DR. PEREZ: Correct. I can speak for our trial in more detail. I personally look at our data on a weekly basis - all the ejection fractions of all patients who have been enrolled to the study and also at any clinical issues that are being raised.

In addition to my weekly review, we have a once-per-month meeting with our Cardiac Safety Board, and that includes three different cardiologists who look at the data with us, along with the statisticians. We issue minutes of each one of these meetings on a monthly basis, and they are submitted to different people outside of our group.

DR. LOVE: So, I'm assuming, at this point, you haven't seen anything of concern?

DR. PEREZ: There's nothing that we have seen that has made us stop the protocol.

DR. LOVE: How many patients have actually been accrued and what's the longest a patient's been on study and where are you in the study right now?

DR. PEREZ: The first patient to N-9831 was enrolled the last week of May of the year 2000, but the majority of the other cooperative groups really activated the trial three to four months after that. So, as of now, we have 700 patients in the study. Accrual is going very well. The interest is high. This is a critical question that we need to answer, so I'm very glad that there's an understanding on how important it is to discuss this trial with patients, so that we can ultimately answer the question whether this agent, trastuzumab, should be moved as part of standard therapy in the adjuvant setting.

DR. LOVE: How many of these patients have completed their therapy?

DR. PEREZ: The protocol for some patients is 18 months, so the numbers are variable between the three arms, but there are many patients who have gone through, now, the twelfth month of therapy of trastuzumab.

DR. LOVE: This is amazing that you're watching this on a weekly basis. I would assume this is the first time that's been done in a prospective manner, in any setting, metastatic or adjuvant.

DR. PEREZ: You're absolutely right. We are accumulating and gathering data that will help us a whole lot in terms of understanding what AC chemotherapy leads to in terms of ejection fractions, because this has never been investigated thoroughly.

DR. LOVE: That's fascinating. I wasn't even thinking about the AC. I was thinking about the Herceptin. But now that I think about it, the AC also.

DR. PEREZ: Actually, we're developing a companion cardiac tolerability study, and NSABP will be conducting a similar trial, too. And, again, this is an example of how we're working very closely together between the breast Intergroup and the NSABP and the National Cancer Institute. What we're going to do is attempt to determine whether we can find some plasma factors that may predict for clinical cardiac toxicity, because there's a lot of literature in the cardiology field regarding the potential value of traponin, traponin T, traponin I, B and P, potential TGF beta, IO6, IO1. So, we're going to be looking at those factors in a prospective fashion to see if any of them correlate with ultimate clinical outcome. We're also going to be looking at another very interesting issue, and it is the correlation between ejection fractions obtained by Muga versus echocardiogram, because this is another thing that we don't know about.

DR. LOVE: So, other than the serum markers and the sonogram and Muga, any other cardiac monitoring?

DR. PEREZ: Yes. As part of the ongoing clinical trials, we are evaluating ejection fractions before study entry, after AC chemotherapy, after paclitaxel chemotherapy, then nine months and 18 months into the treatment. So, we're being very rigorous in terms of looking at ejection fractions. Five times for each patient.

DR. LOVE: Are they getting it both by Muga and ultrasound each time?

DR. PEREZ: In the current parent studies, the physician has discretion. If we had thought that this wasn't safe, I certainly would have never developed the protocol. I feel this agent has really demonstrated that it has a place in the management of patients with HER2 positive breast cancer in the metastatic setting. It's the second targeted therapy developed after tamoxifen and now aromatase inhibitors. So, we must test it appropriately to see whether this drug can improve the cure rate of patients with newly diagnosed breast cancer.

DR. LOVE: When you say you think it's safe, does that mean that you think that actually there isn't going to be cardiac toxicity, or just that you'll be able to pick it up early enough so it won't be a problem?

DR. PEREZ: Well, I hope we do not see any significant cardiac toxicity compared to the standard arm. The way the protocols have been designed is that if we see more than five percent cardiac toxicity in the investigational arms compared to the standard arm, then that would mean that we would stop the clinical trial.

Many women with node-positive, HER2 positive breast cancer die of advanced breast cancer, and we need to try to improve their therapies. We must try to improve their survival rate, and Herceptin is the best agent we have right now that is targeted specifically to this group of women. When I look back at the data from NSABP B-15 - and these data really have not been published in full manuscript, but they are contained within the background of their NSABP-31 trial - we can see the poorer outcome of patients with node-positive, HER2 positive breast cancer, who only receive AC chemotherapy. Even patients with one to three nodes have only a 50-50 chance of being alive and free of disease at five to ten years. So, we have to try to make advances, and these adjuvant studies evaluating Herceptin are the logical steps to take.

DR. LOVE: I'm sure, if a woman has a 50-percent or more chance of dying of metastatic breast cancer than the risk-benefit questions in terms of cardiac toxicity look differently. But I guess I'm still wondering, do you think that Herceptin actually will cause cardiac toxicity?

DR. PEREZ: I hope not. We have done several things in our adjuvant trials to ameliorate the risk of cardiac toxicity, and they include the following. We are not using trastuzumab concurrent with anthracyclines. Number two, we are limiting the dose of doxorubicin to 240 milligrams per meter squared, because when we looked at the data from the pivotal study, the increased risk of cardiac toxicity in terms of congestive heart failure was really seen when the cumulative dose of doxorubicin was greater than 300 milligrams per meter squared. So, we're taking those steps to ameliorate the risk and, in addition to that, we're being very rigorous looking at ejection fractions and recommending discontinuation of therapy based on ejection fractions. So, we're not waiting for clinical cardiac events to recommend discontinuation of Herceptin as part of the adjuvant trial.

DR. LOVE: Any guesses in terms of to what extent, if any, adjuvant Herceptin is being used off protocol?

DR. PEREZ: Well, I hope if it's used, it's very limited, because if someone uses Herceptin outside of the clinical trial setting, they're essentially shooting in the dark - not understanding for how long this therapy should be given, what schedule should be used in combination with chemotherapy, and the potential risks or benefits the patients may derive from such treatment. We have a clinical protocol - actually, we have several clinical protocols available - and I hope that every woman diagnosed with breast cancer really tells the physician, "If I have this bad prognosis, I want to participate in the clinical trial, which will help answer the question."

DR. LOVE: You know, I meant to ask you this question before, so I'm just going to ask you. I'll sort of back in. In terms of using Herceptin in a metastatic setting, do you continue the patient until progression, and do you ever continue the patient after progression when you're switching chemotherapeutic agents?

DR. PEREZ: Well, you're asking another one million dollar question here, Neil. In my standard practice, I use Herceptin until progression or toxicity. The question of whether this therapy should be continued after progressive disease is one we're wrestling with on a day-to-day basis, and I don't know what the answer is. Nobody knows what the answer is. But there will be a clinical trial that will help us answer this question, and we will be joining Dr. Pusztai from M.D. Anderson in his trial. The trial is for patients who have had disease progression to taxane/Herceptin, and the randomization will be to continue on the Herceptin, but add vinorelbine or stop Herceptin and add vinorelbine alone. This study should be embraced by everybody, because it will help us answer this very, very important question.

DR. LOVE: Is it going to be an Intergroup study, or just a M.D. Anderson study?

DR. PEREZ: It's an M.D. Anderson study, and several investigators in the United States will be joining them, because we think it's of significant value.

DR. LOVE: You mentioned the other targeted therapy, which is hormonal therapy, which we don't really think about that much as targeted therapy, but certainly it is the first targeted therapy. Where do you see that heading now? We're seeing the aromatase inhibitors becoming used as first-line therapy. We're hopefully going to see the ATAC adjuvant trial data. Where do you see aromatase inhibitors and endocrine therapy heading over the next few years? And, also, we have, of course, Faslodex coming into the mix. Where do you see all that heading?

DR. PEREZ: Well, it's gratifying, the advances in the hormonal manipulation of breast cancer that have been made over the last few years. Tamoxifen remains our standard as part of adjuvant therapy, although we are starting to look at aromatase inhibitors also in adjuvant studies. We have been contributing to the MA-17 trial led by Paul Goss at the NCI Canada, in which patients who have had five years of tamoxifen, who remain free of disease, are randomized to receive either placebo or an aromatase inhibitor. And, actually, as part of that trial, we are conducting two companion studies evaluating bone and lipid profiles. But, really, aromatase inhibitors have moved to the forefront of the management of patients with metastatic breast cancer which is ER-positive.

The role of Faslodex is going to be interesting, because right now this agent would be used after aromatase inhibitors, but there are studies available showing perhaps equal efficacy and, in some studies, even more efficacy than aromatase inhibitors for management of metastatic breast cancer. In some way the different formulation of Faslodex is a good thing for some patients, because they won't have to remember to use a tablet on a daily basis. On the other hand, they will have to come to the clinic once per month to receive an intramuscular injection. So, it's another exciting area in the breast cancer research and therapy.

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