Select Excerpts from the Interview
DR SWAIN: At ASCO 2005, we heard presentations about three adjuvant trastuzumab trials. One of the presentations was actually a combined analysis of NSABP-B-31 and NCCTG-N9831. I think everyone was stunned by the data and the p-value of 10-12 showing efficacy when you add trastuzumab to AC followed by paclitaxel (Romond 2005a; [1.1]). I was there, and I don’t think there was a dry eye in the place. We have spent our lives working in breast cancer research and have never seen a result like this. It was just spectacular.
After that, the HERA trial was presented, which had a little different design in that it involved the sequential use of trastuzumab. That trial was also very positive (Piccart-Gebhart 2005a). These were also data that were early, without many events. It’s clear that this is changing the paradigm in breast cancer. The hazard rates for distant recurrence in the combined analysis of NSABP-B-31 and NCCTG-N9831 looked as if they’re going down to almost zero. So we may really be curing patients with the use of adjuvant trastuzumab (Romond 2005b; [1.2]).
DR LOVE: In terms of combining the data from the two trials, some oncologists were initially questioning whether that was legitimate. What are your thoughts?
DR SWAIN: The original study design was that each trial would look at the disease-free survival separately. The groups got together before accrual was completed for both of the studies and presented an analysis plan to the FDA in order to get the results sooner. No one had any idea that we’d have the benefit that we do, so they thought they needed the combined analysis to get some results out there.
When they did the combined analysis, it was so spectacular that the results are still significant when the trials are analyzed separately (Romond 2005a; [1.3]). They did not need to do a combined analysis, but they didn’t know that beforehand. So I believe it was clearly legitimate.
DR SWAIN: Dennis Slamon performed this courageous trial, in which he chose to evaluate a nonanthracycline-containing regimen. He conducted the pivotal metastatic trial of trastuzumab, so he was extremely concerned that AC followed by docetaxel/trastuzumab would cause cardiac toxicity. Therefore, he wanted a treatment that did not involve an anthracycline.
BCIRG 006 evaluated AC followed by docetaxel (T) with or without trastuzumab (H) and TCH (docetaxel/carboplatin and trastuzumab). It was a scientifically sound trial.
The interim analysis, conducted in September 2005, was presented at the 2005 San Antonio Breast Cancer Symposium. BCIRG 006 showed a strong benefit associated with the use of trastuzumab — a 51 percent reduction in the risk of recurrence for AC followed by docetaxel/trastuzumab and a 39 percent reduction for TCH (Slamon 2005; [1.4]).
If you evaluated the three curves, ACTH was on top, TCH was in the middle and ACT was on the bottom. There was not a statistically significant difference if you compared ACTH to TCH. However, if you look on the graph, I think it’s clear that TCH is in the middle (Slamon 2005; [1.4]).
DR SWAIN: TOPO II is on the same amplicon as HER2. Mike Press evaluated TOPO II using FISH testing, and 35 percent of the tumors were coamplified for TOPO II and HER2. They found that regardless of the treatment, the patients who had TOPO II coamplification had a better prognosis than those who did not (Slamon 2005).
Furthermore, if you evaluate the patients who did not have coamplified tumors and look at the three treatment arms, you see that it didn’t seem to matter whether they received TCH or ACTH. They all did better compared to the nontrastuzumab-containing arm.
In the smaller group, with the 35 percent of patients whose tumors were coamplified, there was no significant difference between TCH and AC followed by docetaxel (Slamon 2005; [1.5]). They’ve only looked at approximately 2,000 out of the 3,000 patients, so these are preliminary but exciting data.
DR LOVE: The idea would be that if TOPO II is not amplified, you’re not going to need an anthracycline and you won’t need to be exposed to the cardiac risk?
DR SWAIN: That’s the interpretation a lot of people are discussing right now. It is actually a great finding. If this were true, then TCH would be the treatment of choice in those patients, because you obviously don’t want to expose people to a cardiotoxic agent.
They are extremely provocative data, and I’ve heard many people talking about the need to check TOPO II in patients. But I believe right now, we need to hold on. We have very early data with a very small number of events when we start subgrouping. We need the rest of the data with more events, and we need to look at them more carefully.
DR SWAIN: From the four large trials that have been presented (Romond 2005a; Piccart-Gebhart 2005a; Slamon 2005) we have a lot of data supporting the use of taxanes with trastuzumab. In clinical practice, the best plan is to utilize the regimen that you are most comfortable with. AC followed by weekly paclitaxel or by docetaxel are both effective treatments. I personally would recommend every three-week docetaxel rather than weekly docetaxel.
However, I would not recommend vinorelbine. The FinHer study showed that docetaxel had a better outcome compared to vinorelbine ( Joensuu 2005, 2006). I thought that was an interesting finding. With all of the other strong data with the taxanes, a taxane would be my choice. I would use trastuzumab concurrently with a taxane when possible.
DR SWAIN: In NCCTG-N9831, about 10 percent of the patients had node-negative disease (Romond 2005b), and none of those patients had tumors that were less than a centimeter. Probably one of the questions I am asked the most right now is, “What do you do with a patient who has a three-millimeter, HER2-positive tumor?”
In BCIRG 006, about 30 percent of the patients had node-negative disease (Slamon 2005), and some of those patients did have very small tumors. There was not a size limitation, but it’s still, again, limited in number. In the HERA trial, approximately 30 percent of the patients had node-negative disease. The HERA trial was very strongly positive for efficacy with sequential trastuzumab in the patients with node-negative disease (Piccart-Gebhart 2005a; [1.6]).
Hence, strong data support the use of adjuvant trastuzumab in patients with node-negative disease. The nuances of its use are really about the tiny tumors. Do we need to treat those? I attended a meeting last night with Dennis Slamon, and he believes that even patients with the smallest HER2-positive tumors should receive trastuzumab.
I disagree with that a little bit because the data indicate that a patient with a two- or three-millimeter tumor has an extremely good prognosis. I have not been recommending adjuvant trastuzumab for those very tiny tumors because of the risk of cardiac toxicity. It’s not like tamoxifen, with which you have minimal risk. You do have risk, and it requires intravenous therapy for a year.
DR SWAIN: I probably wouldn’t use trastuzumab without chemotherapy. Most likely, even if there’s comorbidity, paclitaxel can be tolerated very well if you use it weekly.
Such a large amount of synergy data exists with trastuzumab, even though the HERA trial is positive with sequential use (Piccart-Gebhart 2005b), I believe Dennis Slamon’s laboratory data that indicate the synergy is important.
So I would try to use paclitaxel with trastuzumab in those patients, and if you’re concerned about the anthracycline, just don’t use that.
DR LOVE: Do you think it makes sense to try to estimate what the chance of recurrence is from that point in time for a patient who is out a year or two or more from her initial treatment?
DR SWAIN: I think the way I would look at it is exactly what you said. You take the risk that they had initially, a year ago, and the benefit of whatever you gave them to see where they are at that point. I think it is reasonable to do that, and you have to do that. I don’t know how else you could do it.
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