I N T E R V I E W  Eric P Winer, MD Dr Winer is the Director of the Breast Oncology Center at the Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

Select Excerpts from the Interview*
* Conducted on June 25, 2005

Tracks 3-4

DR LOVE: Cost and reimbursement issues aside, what are the clinical implications of the ECOG-E2100 bevacizumab data to clinical practice?

DR WINER: I believe the results of ECOG-E2100 are impressive enough that, in the absence of a contraindication to bevacizumab, I would now use it in a first-line setting, optimally in combination with paclitaxel as administrated in the study (Miller 2005a; [2.1, 2.2, 2.3]).

I doubt that the interaction is specific between paclitaxel and bevacizumab, although I’m well aware that when given with capecitabine in more advanced disease, bevacizumab seemed to be less active. I believe that’s probably related to the setting rather than the drug.

DR LOVE: Of course, we have seen bevacizumab work with multiple different agents, particularly in colorectal cancer, and we’ve seen less activity in the second-line setting than the first-line setting in colorectal cancer.

DR WINER: I agree, and it’s one of the reasons why I tend to think this is probably more the setting than the drug.

DR LOVE: What about docetaxel versus paclitaxel, with bevacizumab?

DR WINER: I believe the two taxanes are more similar than they are different, but we have data with paclitaxel and, specifically, we have data with a weekly or almost weekly regimen. In the ECOG trial, paclitaxel was given three out of four weeks.

DR LOVE: What are your thoughts about nanoparticle albumin-bound (nab) paclitaxel with bevacizumab at this time and in the future?

DR WINER: At the moment, I wouldn’t be in a rush to give it with bevacizumab. Once we have a little bit of data in terms of the safety of nab paclitaxel with bevacizumab, I believe it would be a reasonable substitution in a limited number of patients, such as a woman with a contraindication to paclitaxel based on hypersensitivity.

In the CALGB, we actually have planned a study comparing different schedules of nab paclitaxel and paclitaxel. In that study, bevacizumab will be combined with either paclitaxel or nab paclitaxel for those patients who don’t have a contraindication to it.

DR LOVE: Are you currently using nab paclitaxel in your practice?

DR WINER: At our center, we elected to use it mostly, if not exclusively, in patients who have either had hypersensitivity reactions to paclitaxel that we thought were related to the cremophor or in patients who have trouble tolerating steroid premedication.

DR LOVE: Another issue with nab paclitaxel is the shorter infusion time. How much of a benefit is this?

DR WINER: The shorter infusion time potentially has two benefits. One is that it’s better for patients to spend less time in the clinic. We don’t want to take over people’s lives. The second benefit is that, whether it’s in an academic center or in practice, many medical oncologists and oncology nurses are struggling with infusion rooms that are bursting at the seams because of all of these new therapies, so minimizing the time a patient spends in the infusion room is ultimately quite important.

In addition, I believe avoiding steroid premedication is a big deal. Steroids are fine for some people the first or second time you take them, but after a while, the ongoing ups and downs of steroids can be a real problem.

 Tracks 8-9

DR LOVE: Can you provide an overview of the adjuvant trastuzumab data presented at ASCO?

DR WINER: The adjuvant trastuzumab data were pretty impressive and very striking for all of us listening to the presentations (Romond 2005; Perez 2005b; Piccart-Gebhart 2005). I believe what made them that much more striking is that the benefits were seen so early on, although if one thinks about it, given the fact that events in patients with HER2-positive breast cancer tend to be seen early on, maybe that’s not so surprising.

Essentially, there were results from one large study and another analysis of two studies that were combined. The two US studies, which were analyzed together, were the NSABP trial B-31 and the NCCTG Intergroup N9831 trial (Romond 2005; [2.4]). They analyzed the patients on the NSABP trial who were randomly assigned to AC followed by paclitaxel versus those who received AC followed by paclitaxel plus trastuzumab.

The NCCTG trial was more complicated and had a third arm in which patients received sequential trastuzumab. That arm was not included in the combined analysis, so essentially, the combined analysis compared AC followed by paclitaxel versus AC followed by paclitaxel with trastuzumab, followed by trastuzumab for a total of one year. The other trial was the HERA study (Piccart-Gebhart 2005; [2.5]), which was a more permissive study in that it allowed a range of different chemotherapy regimens, and women were simply randomized to trastuzumab or not at the completion of their chemotherapy.

DR LOVE: What did the data show?

DR WINER: The combined analysis showed a very impressive, highly statistically significant improvement in disease-free survival for women who received AC/paclitaxel plus trastuzumab, followed by trastuzumab, compared to those women who received no trastuzumab whatsoever. The reduction in the risk of recurrence was significant — in terms of the hazard ratio, there was a 40 to 50 percent reduction in the risk of disease recurrence. I’m purposely being a little vague about the actual number, because it could change a little over time. I don’t think we should get hung up as to whether it’s a 42 or 46 or 48 percent reduction — the reduction was significant.

Moreover, there was also the early suggestion of a survival benefit, and what’s particularly noteworthy is that this wasn’t a trial of trastuzumab early versus no trastuzumab. It was a trial of trastuzumab early versus almost certainly trastuzumab at the time of recurrence. I believe we have to presume that, if not all, almost all of the women who developed metastatic breast cancer received trastuzumab at that time.

The follow-up is very short from these trials — a couple of years or less — and clearly, we need more follow-up. Whether this difference is maintained and to what extent this leads to a long-term survival benefit remains to be seen, although I think most people assume that there will be a significant survival benefit as we move forward.

DR LOVE: What about cardiac toxicity?

DR WINER: The downside with receiving trastuzumab, apart from the fact that it requires a year’s worth of therapy, is the cardiac toxicity, which was defined as symptomatic congestive heart failure, so we’re not talking about asymptomatic drops in ejection fractions. We’re talking about real problems that we hope can improve over time, but about which we have relatively limited, if any, information about the long-term consequences. I generally tell patients that the risk of congestive heart failure is probably in the range of two to four percent, based on what we know so far, specifically in women who receive AC followed by paclitaxel with trastuzumab (2.6).

There was some suggestion that the cardiac toxicity may be less when trastuzumab is administered sequentially, as in the NCCTG trial where paclitaxel was given and then trastuzumab followed (Perez 2005b; [2.7]). Maybe that relates to a longer period of time from when the anthracycline is given to the beginning of trastuzumab. There was also the suggestion of less cardiac toxicity in the HERA trial, where chemotherapy and trastuzumab were not concurrent (Piccart-Gebhart 2005).

In the NSABP analysis, there was the suggestion that cardiac toxicity was more of a problem in older women, specifically in women who had borderline ejection fractions at baseline versus those who had better, stronger, higher ejection fractions. All of this needs to be sorted out.

DR LOVE: There were some cardiac safety data from the BCIRG trial presented by Dennis Slamon at ASCO. Can you talk about that?

DR WINER: In the BCIRG trial, in the group of women who received docetaxel, carboplatin and trastuzumab, the cardiac toxicity was substantially less than in women who received the anthracycline followed by docetaxel and trastuzumab. I think all of us are very hopeful that nonanthracyclinecontaining regimens will be the wave of the future, but we will just have to wait for the efficacy data. We need those data from the BCIRG trial, and I’m told that we will have those some time over the next several months — certainly at San Antonio, if not before.

 Track 11

DR LOVE: What can we say about the effects of adjuvant trastuzumab in patients with node-negative tumors in terms of clinical practice at this point? How are you going to approach patients in your practice with HER2-positive, node-negative disease?

DR WINER: In the HERA study (Piccart-Gebhart 2005), they included patients with node-negative disease as long as their tumors were greater than a centimeter. A third of the patients participating were node-negative, but we don’t know how many of the events occurred in those patients.

The NSABP trial had no patients with node-negative disease, and in the NCCTG study, patients with node-negative disease accounted for 14 percent of the total population but only six percent of the events (Romond 2005).

I think it’s unlikely that the relative benefits of trastuzumab will be different in patients with node-negative versus node-positive disease. On the other hand, the absolute benefit will differ, because patients with node-negative disease, particularly with small tumors, have a lower risk of recurrence.

In my mind, it’s reasonable to consider trastuzumab for patients who were eligible for the studies. The group of women that I’m a little more cautious about are those with relatively small, ER-positive, node-negative breast cancer. I realize that in the HERA study, a woman with a one- to two-centimeter, ER-positive, node-negative cancer could have been included, but I don’t think we have a sense as to the benefit of trastuzumab in that patient.

I’m not entirely clear what that woman’s risk of disease recurrence would be, particularly with modern hormonal therapy. I’m not saying that woman shouldn’t receive trastuzumab, but I would say that we have to be a little more cautious when we’re talking about the lower-risk patients, since they are at equal risk as the higher-risk patients to experience toxicities.

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