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Two publications in the New England Journal of Medicine last month, a US-based study and a study by the German Breast Group showed the activity of bevacizumab(Drug information on bevacizumab) (Avastin) in early breast cancer. In this interview Gunter von Minckwitz, chairman of the German Breast Group and professor of gynecology at the University of Frankfurt in Germany, discusses the paper he lead-authored, "Neoadjuvant Chemotherapy and Bevacizumab for HER2-Negative Breast Cancer," which showed that bevacizumab in addition to neoadjuvant chemotherapy significantly increased the rate of pathological complete response in patients with early stage HER2-negative breast cancer.
CancerNetwork: Dr. von Minckwitz, could you briefly go over the rationale of both studies, in which patients were given chemotherapy plus bevacizumab before surgery to remove their tumors?
Dr. von minckwitz: So the approach to use systemic treatment before surgery is used more and more in breast cancer, as we can get immediate information about how effective treatment is in the individual patient. The pathologist can examine the tissue that is removed during surgery (after the medical treatment), and tell us how far the tumor has shrunk or disappeared, and we know that those patients where no tumor cell is left—and no tumor cell can be detected by the pathologist—have a highly favorable outcome over the long-term in general. So the idea of our 2 studies was to try to improve, to increase the number of patients, the frequency of patients where no tumor is left at surgery. The idea is based on the studies in metastatic breast cancer: to try to improve the effect of chemotherapy by adding bevacizumab as part of the neoadjuvant treatment. Bevacizumab is an agent that inhibits the building of new vessels around the tumor and therefore can inhibit tumor growth.
CancerNetwork: And just to follow up on the differences between the chemotherapies that were used in these 2 studies: Is that difference just based on the difference between the European versus the US regimens?
Dr. von minckwitz: There are quite some similarities between the treatments that were used—they both used a tetracycline(Drug information on tetracycline) taxane combination sequence as a baseline. The main difference is probably that in the US study there was a second chemotherapy question in the trial. Patients got either 1 of 2 other agents, and so there are some differences. And then the sequence was different in the NSAB American study. First, the taxane was given together with the new agent, and then it was followed by the anthracycline cyclophosphamide(Drug information on cyclophosphamide), whereas in our study we used the more conventional sequence by having first the anthracycline cyclophosphamide, followed then by the taxane.
CancerNetwork: Could you briefly go over what the main take-aways were from both of these studies?
Dr. von minckwitz: In both studies it comes out that the rate of pathological complete responders (PCR)—these are the patients where no tumor was found at pathologic examination after the medical treatment—both trials showed that these PCR rates were higher in those patients that received bevacizumab. Today we always look at how this result is similar in different subgroups of patients, and here we find clear differences between the 2 trials. In the NASB study, the patients that were hormone-receptor positive, HER2-negative, they had a higher rate, more effect from bevacizumab, whereas those patients which were hormone-receptor negative and HER2-negative, they are called triple-negative, they did not see such a clear effect.
In our trial, it was exactly the other way around. We saw a very dominant effect in the triple-negative tumors but almost no effect in the hormone-receptor positive, HER2-negative tumors. So we cannot explain currently why this should be the case. There are theories around it, but they are only hypotheses. At the end it can still be possible that it was just by chance. So what we can clearly say is that there are 2 large studies showing that the addition of bevacizumab can increase the response at surgery, and we of course expect that the additional patients that have now had maximal effect at surgery that they will also now have a longer and better survival.
CancerNetwork: While we wait for the longer term outcomes which is overall survival in these studies, are there other studies being planned to follow up on these results?
Dr. von minckwitz: Yes, we will. Both studies will have follow-up observation of the patients but this will need several years, probably 5 years to get the first results out to show how far this early response translates into a survival benefit. But in the meanwhile, here, the results of the BEATRICE study, which was an adjuvant study that was conducted by Roche in patients with triple-negative disease where they received chemo with or without bevacizumab—similar design, but where the systemic treatment was given after surgery—it is expected that this study reports either this year or next year. This will then give us much more confidence in our results.
CancerNetwork: At this point, neither of these studies reported are practice-changing. We need to wait for the longer-term results?
Dr. von minckwitz: No, no. So far, we are still not sure enough in how far pathologic complete response is reliable enough. We have hints that it is more reliable in triple-negative patients than in the hormone-receptor positive, HER-2 negative patients. There is a project going on currently where all of the evidence from all studies worldwide are being put together to maybe support this, and maybe we will be more confident in our results, but currently we cannot recommend to use these results as practice-changing.
CancerNetwork: Have there been other studies that have shown a benefit for HER2-negative cancer patients early where the treatment was given before, as a neoadjuvant treatment before surgery as in this case?
Dr. von minckwitz: Not with bevacizumab. In the HER2-positive setting, there are a couple of trials where PCR rates could be increased, and we know that this nicely fits to the results that we know from the large adjuvant studies with trastuzumab(Drug information on trastuzumab) (Herceptin). But with bevacizumab and HER2-negative patients, these are the first 2 studies.
CancerNetwork: And other medications besides bevacizumab?
Dr. von minckwitz: The results there are a little bit conflicting. There are earlier studies where this was not so clear. If you go back to the literature, do meta-analyses of trials, then you can demonstrate the differences in PCR rates are more likely to correspond to survival benefits in triple-negative tumors than in the hormone-receptor positive, HER2- negative tumors.
CancerNetwork: We will look forward to the longer-term survival data from your study as well as the US study. Thank you so much, Dr. von Minckwitz for speaking with us today.
Dr. von minckwitz: Yep, thank you!