Select Excerpts from the Interview
DR PICCART-GEBHART: I believe that in the not-too-distant future, we will approach the choice of chemotherapy completely differently. We used to think according to risk, dividing the choice of chemotherapy regimens into the most appropriate for patients with node-positive versus node-negative disease (Piccart-Gebhart 2005a).
We are going to move away from that, because we are entering an era in cancer medicine with the development of superb tools to predict which tumors respond to which drug.
We are not there yet, but this is going fast. The technologies are exploding. If we, the clinicians, are smart enough to design the right studies to validate these technologies quickly, it’s going to change the picture.
Instead of our habit of thinking that six positive nodes means dose-dense chemotherapy, we should look at the profile of the tumor first. And after that we can look at the nodes, because the number of nodes is related to risk.
I certainly would never administer dose-dense chemotherapy to a patient with a Grade I, highly endocrine-responsive tumor with maximum receptors and a very low proliferation index. On the contrary, if I see a young patient with negative nodes but an aggressive tumor with absolutely no endocrine receptors whatsoever, no HER2 and very high proliferation, I would be tempted to use dose-dense therapy.
DR LOVE: Does that same concept apply, for example, to using trastuzumab for patients with lower-risk, node-negative disease?
DR PICCART-GEBHART: This reinforces what I was saying. When a test tells you the tumor will have a good chance of responding to a targeted drug, you more readily use this drug in node-negative patients.
In the adjuvant trastuzumab studies, especially the HERA trial, which had 30 percent of node-negative patients, we saw a substantial degree of benefit from trastuzumab (HERA 2005; Piccart-Gebhart 2005b). The relative risk reduction was the same as among patients with node-positive disease; it was a substantial gain.
As we become smarter about identifying the drugs that work in particular tumors, we will still consider risk in the clinical decision-making process, but it will come second. Risk will be used to evaluate the tradeoffs between efficacy and toxicity, but it will no longer be the first consideration in treatment decision-making.
DR PICCART-GEBHART: The BCIRG 006 study is truly an interesting study. It is original in the sense that it’s the only adjuvant trastuzumab trial that has at least one arm without an anthracycline, the TCH arm. I view the results of this arm as extremely positive. Several of my colleagues were disappointed, because everybody was expecting TCH to markedly surpass all the others in view of some interesting preclinical data (Slamon 2005).
My interpretation of the results is that the TCH arm is almost as good as the traditional AC followed by a taxane and trastuzumab, in terms of efficacy, and it clearly has the advantage of a much reduced risk of cardiac toxicity. I view this regimen as a good option for a woman at very high risk, for example, with many positive nodes, about whom I am very concerned about the cardiac toxicity risk.
DR LOVE: Can you summarize your take on the TOPO II data (Press 2005)? Do you think that right now it would be reasonable to utilize this test as a guide in clinical practice?
DR PICCART-GEBHART: You do some things in medicine before they are completely evidence based. In this case, it is not the first observation. Many others have been recorded, and the data already look pretty solid. So although you certainly cannot write that in a textbook or in guidelines, I will be tempted to use it for my patients.
DR PICCART-GEBHART: Women were allowed to enter the HERA trial if the tumor size was greater than one centimeter. This was the only criterion. We didn’t require other aggressive features — it was purely based on pathological size. Of course, now the problem we have is with young women coming to us with eight-millimeter tumors and negative nodes. Usually, when you look at the pathology, you see other features of aggressiveness — for example, a high proliferation rate, Grade III tumors and so on.
Personally, I don’t see why these women would not derive a substantial benefit from trastuzumab. Provided these women are well informed about cardiotoxicity risk, of course, we are discussing with them the possibility of trastuzumab.
DR PICCART-GEBHART: That’s a very difficult question. As we continue to follow the women in the control arms of the adjuvant trastuzumab trials, we will better understand the hazard rates over time. It’s clear from the data we collected in HERA that women are at very high risk in the first two years — they have a high risk of experiencing a relapse every year (HERA 2005; Piccart-Gebhart 2005b; [3.1]). So up to two years, if a woman wants to start the drug, it makes sense to do it. Beyond two years, I have no idea.
Our French colleagues demonstrated this with tamoxifen, another targeted agent. Dr Goss also presented fascinating data at the San Antonio meeting with delayed introduction of letrozole. So you start wondering whether a smart targeted drug will still provide benefit when you introduce it somewhat later. It would be interesting to design a trial looking at that (Goss 2005 a, b).
DR PICCART-GEBHART: That’s a difficult question, and I don’t think I have an answer. I am embarrassed by the fact that it’s not possible to identify the subset of patients that really benefits from the drug. To me, using such an expensive agent for metastatic disease without the possibility of targeting the drug is a little bit problematic.
Putting cost aside, I would use clinical judgment and I would probably be comfortable with the use of the drug for very aggressive, rapidly proliferating tumors with visceral metastasis for which, clearly, endocrine therapy cannot be beneficial.
I have no personal experience with the drug, because we have not had access to it in Europe, with the exception of a few investigators involved in Phase I/Phase II trials. It is also not reimbursed. So not having experience makes it difficult to answer.
But in my experience, sometimes women are exposed to endocrine treatments in sequence for prolonged periods of time. The day they exhaust all these possibilities, they are endocrine resistant, and you believe that chemotherapy is going to work, because they haven’t seen it. My impression is that it doesn’t work that well in that setting.
Based on that experience and given that there is this very well-conducted, highly positive randomized trial, I would have few problems prescribing bevacizumab combined with a taxane. If I were to use this drug today, I would use it with weekly paclitaxel as it was given in the ECOG-E2100 trial (Miller 2005; [3.2]).
DR PICCART-GEBHART: The majority of first-line chemotherapy in Europe is taxane-based, because we give a lot of anthracyclines in the adjuvant setting. Many people use taxanes as soon as there is visceral disease — either docetaxel or paclitaxel.
For patients who received adjuvant taxanes, we tend to use them again if there is a long treatment-free interval.
DR LOVE: What about if there isn’t a long treatment-free interval or if the patient progressed on a taxane?
DR PICCART-GEBHART: Then it would depend a little bit on the amount of anthracycline they had, and whether we can possibly use a liposomal anthracycline. Capecitabine, clearly, is among our choices. Vinorelbine may be another option.
DR LOVE: What has been your experience with capecitabine in the metastatic setting?
DR PICCART-GEBHART: For some patients this can really be a fabulous treatment. I have a few patients who have been on capecitabine for more than two years with very good stabilization of the disease, manageable toxicities and good quality of life. When the drug works, it can be really tremendously useful.
DR LOVE: How do you approach dosing?
DR PICCART-GEBHART: I usually start at 2,000 mg/m2. In a very frail patient I might even start with 1,800 mg/m2. I never start with 2,500 mg/m2 — I reduce the dose.
DR PICCART-GEBHART: I have been very impressed by the results of MA17 (Goss 2003, 2005a; Ingle 2005; [3.3]). To me, this is an indication that hormone receptor-positive breast cancer is extremely difficult to cure — these women are at risk of relapse five, seven, 10, even 12 years after diagnosis. On the other hand, we clearly have an increasing number of very active endocrine agents.
I am biased. I believe that the optimal therapy for these women in the future will be a very smart sequence of endocrine agents, covering at least 10 years. Because of this bias, I don’t like the idea of giving an aromatase inhibitor to everybody up front, because I don’t know what to give after an AI, and I don’t think an aromatase inhibitor will cure all these women. In addition, some patients will develop resistance to the drug.
In view of that, I tend to look at the profile of the tumor. If I’m dealing with a highly endocrine-responsive tumor with little worry about early relapse on therapy — a situation in which both ER and PR are very high, the proliferation genes are very low, the tumor is Grade I, and there is no HER2 overexpression — I believe there is a very low risk that the patient will relapse if you put her on tamoxifen for two years.
DR LOVE: What if the patient has node-positive disease? Do you believe that in the first two or three years there is an excess risk of relapse in those patients on tamoxifen?
DR PICCART-GEBHART: It might be that you will have a few early relapses, but on the other hand, given that the sequencing strategy is so effective and allows you to go for a seven- or eight-year treatment period, you might recover these losses later. The sequencing strategy might be more effective in the long term.
Of course, this is pure speculation and nobody knows. But I don’t think it’s so simple. An aromatase inhibitor for everybody up front is also expensive and cannot be afforded in many parts of the world. Certainly, this might not be the best strategy for everyone.
DR LOVE: How do you factor endometrial cancer and deep vein thrombosis versus potential effects on bone into your decision?
DR PICCART-GEBHART: It is very important. Clearly, before making a decision about adjuvant endocrine treatment, I do an in-depth evaluation of lipids, cardiovascular status and bone health.
All of these considerations need to be factored into the decision-making process.
DR LOVE: Putting aside the cost issue, what would you recommend for a 70- year-old woman with an ER/PR-positive tumor with two positive nodes?
DR PICCART-GEBHART: This is clearly a woman for whom I am going to investigate the family history, look at lipid levels, ask for bone densitometry, ask whether she already has arthralgia and make sure that she has no history of deep venous thrombosis and embolism in the family.
If she’s in very good health, very active, very fit, and I don’t have to worry too much about bone and about cardiovascular disease, I would start with tamoxifen and go after that to an aromatase inhibitor, despite her two positive nodes. And this woman can still have a long life expectancy.
Starting with four positive nodes, I am more reluctant to go for tamoxifen. But a patient with one to three positive nodes is still in an intermediate risk group in the absence of HER2 overexpression.
DR LOVE: If we were able to conduct an international Patterns of Care study, I would expect to see a big difference in terms of US versus non-US physicians in how they answer that case.
DR PICCART-GEBHART: I agree. Although even in the US I see the controversy. I know colleagues who are very much in favor of the sequencing strategy in selected patients and others who are really in favor of an aromatase inhibitor. Some have killed tamoxifen and don’t use it anymore.
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