Kathy D. Miller, MD; Gunter von Minckwitz, MD, PhD


December 19, 2011

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Kathy D. Miller, MD: Hello. I am Kathy Miller, Associate Professor of Medicine at Indiana University School of Medicine, in Indianapolis. Welcome to Medscape Oncology Insights in Breast Cancer, coming to you from the 2011 San Antonio Breast Cancer Symposium.

Joining me is Dr. Gunter von Minckwitz, Chair of the German Breast Group Research Institute, and Professor of Gynecology at the University of Frankfurt, in Frankfurt, Germany. Welcome, Gunter.

Gunter von Minckwitz, MD, PhD: Hello, Kathy.

Switching Chemo: GeparTrio

Dr. Miller: I would like to talk with you today about chemotherapy in the neoadjuvant setting. Your group has had a longstanding research interest in this area, and particularly at this meeting you brought us updated results of the GeparTrio[1] and the GeparQuinto[2] studies. We have talked about those studies before, but it has been a while. Can you remind us of the design of the GeparTrio[1] study?

Dr. von Minckwitz: The GeparTrio design aimed to individualize treatment. We wanted to take advantage of the possibility of measuring interim response and developing treatment strategies according to this response. Patients who did not respond (in whom the tumor did not shrink more than 50%) were either continued on the same treatment, or they were switched to a noncross-resistant chemotherapy. The responding patients were randomly assigned to either 6 or 8 cycles of chemotherapy.

Dr. Miller: This was based on the early hopes of what we could do with therapy in the neoadjuvant setting, to use the patient's individual response assay, and then alter treatment -- hopefully, in ways that would help patients do better. Yours was one of the first and largest studies to see if making those changes made a difference. Let's talk first about the good side -- the patients who were responding, in what was really a duration question.

Dr. von Minckwitz: This is a 2000-patient trial -- quite a huge effort -- and the trial accrued patients 5-8 years ago. We were very disappointed when we saw that there was no difference in pathologic complete response (pCR). We saw a difference between the nonresponding and the responding patients, but not between the randomized arms. Of course, we wanted to see if anything happened in long-term outcomes, and we presented at this meeting the 5-year survival data for this trial. Surprisingly, better outcomes were seen for the response-guided arms, even a survival benefit for those patients, either those who switched to the noncross-resistant treatment or those who got the longer treatment (the higher number of cycles). Even disease-free survival improved in the randomized groups. There was a benefit in the sensitive population for 2 further cycles, as well as a benefit for the nonresponding patients when they switched.

Dr. Miller: I am glad to hear that you were surprised, because I was really surprised. We have all accepted that pCR is a good surrogate for those longer-term outcomes, and that if there is no difference in pCR, there is probably not much hope for disease-free and overall survival.

Dr. von Minckwitz: Exactly.

Explaining the Unexpected

Dr. Miller: I was not expecting those results at all. How do you explain these results?

Dr. von Minckwitz: Of course we had the same thoughts, and therefore we went into more depth with the data. We are not talking about all of these different breast cancer subtypes. We used the St. Gallen definitions to group these patients into luminal As, luminal Bs, HER2-positive luminal Bs, and HER2 negatives, HER2-positive nonluminals, and triple negatives. We used just hormone receptor status, HER2 status, and grade; so far, we do not have data on ki67. Then we had this surprising result (which fit nicely into what we have seen before in other studies and also with the results of our meta-analysis) that the benefit derived almost exclusively from the luminal tumors.

Dr. Miller: These are patients in whom pCR is not very common.

Dr. von Minckwitz: Exactly. It is not very common, but even if there is a pCR, we have shown that it doesn't make a difference, so pCR is not prognostic in these patients, and therefore the circle is closing. Because pCR is not valid, we could not predict this treatment effect by looking at pCR, so we had to wait for a long-term outcome. No difference was seen in HER2-positive nonluminals and in the triple negatives. These patients did not gain from switching treatment, or from longer treatment, but their prognosis is strongly dependent on pCR, and so the prediction was correct: There is no benefit -- no improvements in pCR, no benefit in survival -- so it makes no sense for these patients.

Dr. Miller: That part really came together as a nice explanation. For subgroups in which pCR predicts long-term outcome, no difference was seen in pCR or long-term outcome, but in the luminal subgroups, in whom pCR has not been a good surrogate for outcome and is less common, no difference was seen in pCR, but there was a longer-term outcome. What was probably less intuitive to me is that you were looking entirely at chemotherapy, and you essentially identified a benefit of altering the chemotherapy in a group of patients who I wouldn't have expected to gain much from the chemotherapy in the first place.

Dr. von Minckwitz: In the adjuvant setting we were never able to do such a thing. In many trials, we were perhaps facing the wrong direction. In adjuvant trials, we are always triggered by these high-risk patients. Most trials have only a short follow-up, most events occur in the first 2 years (and these are the triple negatives, the HER2-positive patients), so the magnitude of our results in the adjuvant setting are based on that. To find out which is the right strategy for the luminals was quite difficult. In the neoadjuvant setting, the option of individualizing or personalizing the treatment, according to this initial response, is perhaps the better approach.

Adding Everolimus: GeparQuinto

Dr. Miller: Let's shift to the GeparQuinto trial,[2] which in some ways followed a similar strategy -- you looked at initial response, and patients who were not responding would switch to a different therapy. In the GeparQuinto trial, the question you were testing was whether adding a novel molecularly targeted agent, rather than just altering the chemotherapy, improved the results. The GeparQuinto trial is large and complicated in its design, but we will focus just on the HER2-negative patients and the design for that subgroup.

Dr. von Minckwitz: On the basis of the GeparTrio results, we thought it does not make sense to just switch to another chemotherapy. We thought that these tumors were resistant to chemotherapy, so we have to look for a resistance-modifying agent. The agent that was available for us to use was everolimus, which is not only a response-modifying agent, but it has multiple actions, so it was something that we thought might help. We randomly assigned patients who had not responded to epirubicin/cyclophosphamide (with or without bevacizumab) to weekly paclitaxel, with or without everolimus, for another 12 weeks. The endpoint of the study was pCR.

However, the pCR rate was not changed; it remained low. Our assumptions were exactly met; the pCR rate was 5%, which was what we expected.

Dr. Miller: You have identified a group that is resistant to epirubicin/cyclophosphamide, so although paclitaxel has a different mechanism, other studies had suggested that this was not a group that had a huge amount to gain. However, you must be questioning how to interpret these results in light of the long-term follow-up of the GeparTrio trial.

The Wrong Endpoint?

Dr. von Minckwitz: This is exactly what I am thinking -- did we choose the right endpoint?

Dr. Miller: Have you looked at the difference in pCR rate based on subtype, to get hints of whether long-term outcome might be there?

Dr. von Minckwitz: We haven't done that so far. This group is enriched by luminal patients, so there might be something in there. However, it is only 400 patients, so it is much more difficult to draw conclusions.

Dr. Miller: Long-term follow-up is going to be difficult with only 400 patients.

Dr. von Minckwitz: Yes, except if the treatment effect is as strong as we have seen from the BOLERO-2 study,[3] which focuses on luminal patients. It is endocrine treatment with chemotherapy, but at the end it is possible that with the longer follow-up, we will see differences. Although this trial is a negative trial (the primary endpoint has not been met), for me, it is not the end of the story.

The Power of Neoadjuvant Studies

Dr. Miller: These were truly tour-de-force works in this area, and they nicely highlight for our audience the potential power of doing studies in the neoadjuvant setting. Particularly with the GeparTrio results in those luminal patients, the potential to improve outcomes with their chemotherapy is something that many of us thought might not have been possible.

Dr. von Minckwitz: We now have a much stronger argument for the use of neoadjuvant treatment, because we can really improve outcomes only by using neoadjuvant treatment. This is something that we like to see, and feedback from many colleagues suggests that they may have to recapitulate their strategies and perhaps use it more frequently.

Dr. Miller: Gunter, thank you for coming in and joining us today. And thanks to you, our audience, for joining us for this edition of Medscape Oncology Insights. This is Kathy Miller, at the 2011 San Antonio Breast Cancer Symposium.


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