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You are here: Home: BCU 6 | 2008: Martine J Piccart-Gebhart, MD, PhD

Martine J Piccart-Gebhart, MD, PhD

Tracks 1-17
Track 1 HERA trial: Two years versus one year of adjuvant trastuzumab
Track 2 Treatment for patients with node-negative, HER2-positive tumors under one centimeter
Track 3 Influence of ER status on patterns of recurrence in HER2-positive BC
Track 4 Use of nonanthracycline-containing chemotherapy regimens with adjuvant trastuzumab
Track 5 Rationale for the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial
Track 6 Side effects and toxicity of lapatinib with paclitaxel and trastuzumab
Track 7 Equipoise in enrolling patients with high-risk BC on the ALTTO trial
Track 8 Lapatinib with or without trastuzumab in heavily pretreated mBC progressing on trastuzumab
Track 9 Anti-HER2 therapy for recurrence after adjuvant trastuzumab
Track 10 Activity of lapatinib in treating CNS metastases
Track 11 ABCSG-12: Adjuvant ovarian suppression with tamoxifen or anastrozole, with or without zoledronic acid, in premenopausal women with ER/PR-positive BC
Track 12 Seed and soil hypothesis and the antitumor effects of zoledronic acid in ABCSG-12
Track 13 Clinical implications of the zoledronic acid data from ABCSG-12
Track 14 Impact of ABCSG-12 on clinical decision-making regarding adjuvant hormonal therapy for premenopausal patients
Track 15 Extended adjuvant endocrine therapy for premenopausal women with high-risk BC
Track 16 Clinical use of long-term adjuvant hormonal therapy for postmenopausal women with ER/PR-positive BC
Track 17 Viewpoint on the efficacy of bevacizumab in mBC

Select Excerpts from the Interview

Tracks 2-3

Arrow DR LOVE: How do you treat patients with smaller, node-negative, HER2-positive tumors?

Arrow DR PICCART-GEBHART: This is a real problem in daily clinical practice. Given that these patients were not allowed to enter the adjuvant trials, we have no data. I interviewed my colleagues and discovered that many do what I do, although it’s based strictly on intuition. I am offering trastuzumab to women who have tumors between five millimeters and one centimeter. For tumors smaller than five millimeters, I am less comfortable with such a recommendation.

So, although tumor size has clear prognostic significance, I still believe the biology is bad. You could argue that these women should only receive an anthracycline-based chemotherapy regimen. However, trastuzumab is such an elegant therapy.

Arrow DR LOVE: Would you consider trastuzumab alone, without chemotherapy, for those patients?

Arrow DR PICCART-GEBHART: No, I would not do that presently because no data exist for that approach either. You would be doing two things that are not at all evidence based. For these women, I prefer the treatments that have been tested.

Arrow DR LOVE: Does ER status affect your decision with the smaller tumor?

Arrow DR PICCART-GEBHART: Not really. In the HERA trial, we saw a different pattern of relapse in women who had ER-positive versus ER-negative tumors (Untch 2008; [2.1]). The cancer in women with ER-negative disease tends to recur early when they don’t receive trastuzumab. We observed this in the control arm of the trial. For women with ER-positive disease who were not receiving trastuzumab, we do not see an early peak of relapse. The relapse rate also appears to be lower, although it could simply be a time effect. I don’t believe we can make any treatment decision based on this observation. It could be that the patients with ER-positive disease also relapse at a high rate, but it happens a little later.

Track 4

Arrow DR LOVE: Can you discuss the issue of anthracycline-versus nonanthracycline-containing chemotherapy for node-positive, HER2-positive disease?

Arrow DR PICCART-GEBHART: That’s a hot topic. In Europe, we are selecting the type of chemotherapy based on risk factors for cardiotoxicity, including age, obesity, poorly controlled hypertension and a left ventricular ejection fraction that is on the low end of the normal range prior to initiating therapy. For patients who are at a higher risk for cardiotoxicity, it is reasonable to choose a nonanthracycline-based chemotherapy.

I stick to TCH, the regimen that has been piloted in the BCIRG 006 study (Slamon 2006). It is important to be able to clearly explain to patients the side effects they can expect with this regimen.

Arrow DR LOVE: How would you treat a 38-year-old woman who has five positive nodes and is otherwise perfectly healthy?

Arrow DR PICCART-GEBHART: We have two options. The five positive nodes are worrisome and indicate a higher risk for an early relapse. You do not want to administer a six-month chemotherapy regimen and then start trastuzumab. It makes sense for such a woman to receive TCH or utilize our European approach, which is three cycles of FEC — this is anthracycline based but only three cycles — and then move on to a taxane, which can be docetaxel or paclitaxel, administered concomitantly with trastuzumab.

2.1

Tracks 5-6

Arrow DR LOVE: Can you discuss the ALTTO adjuvant trial?

Arrow DR PICCART-GEBHART: When we design these trials, we have a responsibility to ask interesting questions. With the ALTTO study, we felt that it was important to compare the relative merits of two anti-HER2 treatments (2.2).

The single-agent lapatinib arm has not made everyone comfortable, but we believe that the lapatinib data in metastatic breast cancer are encouraging. It is important to examine what a small molecule administered orally can do, as opposed to an antibody that must be administered in a hospital setting. In some countries in the world, it might be a problem to go to the hospital every three weeks for a full year.

The other arms are exciting. One of them is exploring the sequence of the two drugs — three months of trastuzumab, a short washout period and then lapatinib to complete a year of treatment. The third arm, which could be the winner, is the combination of the two agents.

Chemotherapy can be introduced in two ways. One is to administer the chemotherapy first, and you have a lot of flexibility in the choice of chemotherapy regimen. The second option is the concurrent administration of the biologics with paclitaxel. Paclitaxel was chosen because the only safety data available at this time are with paclitaxel. We will probably introduce an option for docetaxel in the near future because we are beginning to see data there.

2.2

Currently, the ALTTO trial is requiring patients to receive anthracyclines, but this may also change. We don’t want to be in a situation when the trial is finished in which people tell us anthracyclines are no longer needed. We are hoping to be able to allow regimens such as TCH to be used in the trial.

Arrow DR LOVE: What do we know about the safety of the paclitaxel/lapatinib combination and the combination of paclitaxel with lapatinib/trastuzumab?

Arrow DR PICCART-GEBHART: Initially we chose the doses on limited data, which now have been expanded. It has become apparent that some women experience severe diarrhea with the doses we initially selected. Although it is possible to manage this type of toxicity in sophisticated cancer centers, this trial should mean something to practices all around the world.

We made the decision to reduce the dose of lapatinib to 750 milligrams instead of the 1,000-mg dose, but we did not touch the dose of paclitaxel. We know from experiences in two cancer centers, Memorial Sloan-Kettering (Dang 2008) and the Mayo Clinic in Florida, that when you reduce the dose of lapatinib, you can continue with the treatment. We assume that if we start with this lower dose, the toxicity will be acceptable. We will monitor patients extremely closely in the adjuvant study. We hope that this is not going to compromise efficacy, but we could not run the risk of toxic deaths in a study such as the ALTTO trial.

Tracks 11-12

Arrow DR LOVE: Can you discuss the main findings of the ABCSG-12 study?

Arrow DR PICCART-GEBHART: This is a fascinating trial. If the results can be duplicated in a second study, I believe we will be entering a new era in the fight against the disease. The focus will shift away from the tumor toward the importance of the host.

We have to remember that ABCSG-12 was highly selective with its entry criteria (Gnant 2008). It was a trial for premenopausal women with endocrine-responsive breast cancer whose physicians were comfortable not administering chemotherapy. The first randomization was between two endocrine treatment strategies. The second randomization was to zoledronic acid every six months or placebo.

Arrow DR LOVE: A fair number of patients with node-positive disease were enrolled on this study, yet the five-year relapse rate was approximately six percent, which is striking.

Arrow DR PICCART-GEBHART: That’s not so surprising to Europeans because we have been defending endocrine therapy for a long time. For women who do not have massive nodal involvement and whose tumor is highly endocrine responsive, we are convinced that the benefit of chemotherapy is small or nonexistent.

We have to remember that this was not a broad population but a highly selected population. Therefore, we have to wait for confirmation from one of the other trials that has examined a larger population. When I evaluated all the preclinical work during the past 10 years that exists on bisphosphonates, particularly zoledronic acid, I began to believe that these drugs might have potential beyond ER-positive breast cancer.

I am optimistic. I believe the AZURE trial will confirm these data. AZURE is a trial for patients with node-positive disease that can be ER-positive or ER-negative. It includes younger and older women, so it will be more representative of the breast cancer population. The bisphosphonate is also administered in a more intensive fashion. If this trial is positive, I believe this agent will become a standard treatment.

Arrow DR LOVE: ABCSG-12 reported a striking 35 percent decrease in relapse rate (Gnant 2008). What was interesting was that it wasn’t only in bone. It was in contralateral primary tumors and metastatic disease. Can you talk about the seed and soil hypothesis that you presented in your ASCO discussion of this paper?

Arrow DR PICCART-GEBHART: This requires that we speculate about breast cancer progression models. The seed and soil hypothesis is that breast cancer cells leave the breast much earlier than we think, find a niche in bone and from there metastasize to other organs and even go back to the initial site where they came from in the breast.

We think this occurs only in a certain type of patient. It is similar to what Larry Norton has been showing recently (Norton 2006), even before knowing about the results of the Austrian trial.

The ABCSG-12 trial is challenging our belief about this stepwise progression model, in which the cancer cell is first in the breast and then travels to the nodes and elsewhere. Maybe that’s not at all what is happening in the real world.

Track 13

Arrow DR LOVE: In your ASCO discussion, you cautioned people about translating these data into practice. Right now, do you discuss this with your patients as a possibility?

Arrow DR PICCART-GEBHART: I am talking to my patients who are in exactly the scenario of the Austrian study — for example, patients whom I am treating with goserelin and tamoxifen. I’ve been telling my patients that I am waiting for the presentation of a second study, I hope by the end of this year.

So I’ve scheduled appointments for these patients for the beginning of 2009, and I’ve asked them to go to a dentist beforehand for a baseline evaluation because of the small risk of osteonecrosis of the jaw (ONJ). Although ONJ was not observed in the Austrian study, we know that it is a potential complication of bisphosphonate therapy.

Again, I don’t know what will happen at the beginning of 2009, but if the second study is positive, then it’s an easy decision. We will start administering this agent to patients. If AZURE is not reported at San Antonio, then women have to make a decision for themselves after the full explanation of potential benefits and risks.

Track 16

Arrow DR LOVE: What are your thoughts about continuation of hormonal therapy for postmenopausal patients who have received five years of an aromatase inhibitor?

Arrow DR PICCART-GEBHART: I belong to the group of people who view hormone receptor-positive breast cancer as a disease that might be difficult to cure and might require lifelong treatment. If we are able to conduct good translational research in some of the big endocrine therapy trials, and if we are able to complete pharmacogenetic studies, we might be able to identify those patients who are at risk for long-term relapses.

Perhaps not all women with hormone receptor-positive breast cancer are at risk for long-term relapses, but right now, we don’t have a way to identify who is at risk and who is not. In our practice, we observe women who have these relapses occurring nine, 12, 15 years after initial therapy.

If you believe in the long-term risk, then stopping an aromatase inhibitor after five years doesn’t make a lot of sense. I am trying to continue treatment for up to seven, eight, sometimes 10 years. I recognize that we have few data, but it’s a question of philosophy and how you view this disease. Unfortunately, this is a disease that probably has to be viewed as a chronic one, requiring continuous endocrine manipulation.

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EDITOR
Neil Love, MD

INTERVIEWS

Paul E Goss, MD, PhD
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Martine J Piccart-Gebhart, MD, PhD
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TUMOR PANEL CASE DISCUSSION
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INTERVIEWS (continued)

Erica L Mayer, MD, MPH
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Maria Theodoulou, MD
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