2013 San Antonio Breast Cancer Symposium (SABCS)

Comment on HER2 research: NeoALTTO trial, BETH study and immune cell levels predicting outcomes

Dr Jennifer Litton - MD Anderson Cancer Center, Houston, USA

We heard three presentations from three investigators looking at HER2 positive breast cancer. The first was done by Dr Martine Piccart-Gebhart from the Jules Bordet Institute and she looked at the NeoALTTO study. This was a neoadjuvant study that has been previously reported by Dr Baselga that looked at taxane plus lapatinib versus taxane plus trastuzumab versus taxane plus the combination of lapatinib and trastuzumab followed by surgery followed by FEC chemotherapy. That showed that the combination of the two anti-HER2 agents was superior as far as PCR and that was already presented. What Dr Piccart presented was long-term follow up after three years; it was not powered for overall survival but what was intriguing, and the take home message of her trial, is that PCR as a surrogate endpoint continues to be statistically significant to look at overall survival and event free survival. That’s important because we are now seeing a lot of trials being designed around neoadjuvant therapy and pathologic complete response in order to get drugs through the approval process. It can be done quicker, it can be done cheaper because you don’t need as many patients and hopefully will help us design trials as we move forward that will also be adaptive. So for those patients who aren’t responding or not having the response that we’re hoping, we can move to other trials, other treatments to try to get a better response.

The second doctor was Dr Sherene Loi from Melbourne and she presented her work on tumour infiltrating lymphocytes. We have known for some time, not just in HER2 positive breast cancer but also in triple negative breast cancer, that those tumours that have infiltrating lymphocytes are more responsive to therapies and those patients do better. She showed that as well in HER2 positive. Also, interestingly, looking at different expression of some of the checkpoint blockade molecules such as PD1, CTLA4, and how those may be affecting outcomes. Very interesting in her work looking at mouse models putting the combination of trastuzumab and these anti-checkpoint blockade agents and showing synergy and I think that’s very intriguing and exciting moving forward.

The last presentation was Dr Dennis Slamon from UCLA and he presented the results of the BETH trial. It was a neoadjuvant trial looking at chemotherapy with Herceptin plus or minus the anti-angiogenesis agent bevacizumab. The take home point from this study is that bevacizumab added no additional benefit and only toxicity so at this point bevacizumab will be unlikely to move forward in this group of patients.

With the first trial you mentioned, are there any costs that need to be considered?

Absolutely, lapatinib does have toxicities, it can have significant rash, diarrhoea, some liver toxicity. The thought of putting the two agents together is what was really novel and what was available to the investigators at the time of that trial. Since that time there have been several new anti-HER2 agents that are very exciting, specifically pertuzumab that has been already presented in the NEOSPHERE trial and led to our ability to use it in the neoadjuvant setting for our patients in the United States at this point. Also other drugs such as TDM1, and they are going to now move forward into the neoadjuvant setting. So the idea of combination HER2 therapies will be exciting and on-going at this point.

Which HER2 patients are selected for  neoadjuvant treatment?

It used to be that neoadjuvant therapy was really reserved for patients who had very locally advanced tumours with the idea to shrink it down so that patients could become more of a surgical candidate. But I really feel that in the last decades it has really changed to anyone that we can measure the tumour we would like to give the chemotherapy or targeted therapy while the tumour is intact because that provides us very important biologic information. If we’re shrinking the tumour that we can see and why we’re really giving the chemotherapy is to shrink the microscopic disease that we can’t see, which is the dangerous part that might spread to other parts of your body, if we’re shrinking what we can see we’re hopefully shrinking what we can’t see. For those patients that aren’t responding and the tumour grows, we’re not going to waste that person’s time or toxicity of continuing a therapy that’s ineffective and we can move rapidly to a therapy that can shrink the tumour before we take them to surgery. Because what we’ve shown over and over is that even though PCR is a good endpoint for overall survival, also those patients who are actively responding to therapy at the time we take them to surgery also have a better outcome than those who do not.