ESMO 2012, Vienna, Austria

Standard of care for neo-adjuvant therapy in HER 2 and triple negative subtype

Dr Fatima Cardoso – Champalimaud Cancer Center, Lisbon, Portugal

We discussed in this educational session the standards of care for neoadjuvant therapy and we discussed it for the three main types, or subtypes, of breast cancer. I discussed it for the HER2 positive and the triple negative subtype and then Marco Colleoni discussed also for the luminal type of breast cancer. There was also a discussion about the surgical aspects or surgical challenges that the neoadjuvant therapy poses.

 Regarding the neoadjuvant therapy for HER2 positive breast cancer, we have made quite a few advances in these last years. The first advance was, of course, with the use of trastuzumab in the neoadjuvant setting. What we are lacking there and is still something that could be investigated, although not very easily done these days, would be to understand if it is important to give this drug in the neoadjuvant setting or in the adjuvant setting. I think it will be hard to have a direct comparison nowadays and probably we will need to have indirect evidence from the results that are out there showing a much higher pathological complete response rate when we add this drug in the neoadjuvant setting. Although the pathological complete response rate is not always linked to long-term outcomes it is in the majority of cases and therefore we could have an indirect evidence of the benefit of starting these biological agents as early as possible in the neoadjuvant setting.

There are quite a few trials, randomised trials, relatively big trials, evaluating not just trastuzumab but also lapatinib, the combination of both and also pertuzumab, a new monoclonal antibody, anti-HER2 and also the combination of trastuzumab and pertuzumab. We went through all these studies pointing out some important evidence. One of them already mentioned the importance of blocking this pathway early on, so starting in the neoadjuvant setting, increasing the pathological complete response. Then we discussed what would be the best chemotherapy to combine it with and there are studies evaluating starting with taxanes and then moving on to anthracyclines before or after the surgery; there are studies evaluating a more usual way of giving the chemotherapy, starting with anthracyclines and then with the taxanes. Basically we see always the same with the increased benefit or increased pathological complete response rate when adding these agents. Some important information for clinical practice is that we can use these agents combined with anthracyclines; for a long time there was the fear of cardiotoxicity but as long as we use doses of anthracyclines that are not as high as when we use it alone, the cardiac safety of all these trials is quite reassuring that we can combine these agents.

There are also several trials evaluating what is called the dual blockade, so the use of two anti-HER2 agents, be it trastuzumab lapatinib or trastuzumab pertuzumab. They all show also the same thing, the benefit of dual blockade when compared with each of these agents alone. Also in all the trials that had at least three arms, let’s say trastuzumab, another anti-HER2 or the dual blockade, we can see that so far, with the data we have and despite the fact that these are limited data, the combination of chemotherapy trastuzumab seems to be more efficacious than chemotherapy lapatinib or chemotherapy pertuzumab.

Also in the pertuzumab NeoSPHERE trial, there was a very interesting arm with just the two biological agents, no chemotherapy. The pathological complete response rate was 16%, which is something quite interesting for a non-chemotherapy regimen and raises some other possibilities. Also there was another study in the US evaluating lapatinib, trastuzumab alone with no chemotherapy also with a PCR rate, very interestingly, of 30%. Of course we are not saying that we can, at this moment in time, treat patients without chemotherapy but it’s something to think about that perhaps we need to dissect more who are the patients who absolutely need chemotherapy in this setting. So a lot of advances have been made in this area of the HER2 positive subtype.

The other subtype I had to discuss was triple negative breast cancer. Unfortunately, the advances are not so important or not so efficacious for our patients. There is a lot of discussion around platinum compounds and the potential higher benefit of this type of chemotherapy for triple negative breast cancer. The available data shows that for sporadic triple negative breast cancer these agents are not better than the standard treatment of anthracyclines and taxanes. They provide a pathological complete response rate in the range of 15%, not higher. The exceptions are those triple negative breast cancers that are linked to the BRCA1 mutation. In those specific subtypes then there is a very high rate of pathological complete response. So the recommendation of all the consensus guidelines conferences, both in Europe and in the US, is that at this day in time the regimens that you use in the neoadjuvant setting should be the same as in the adjuvant setting and this regimen should include an anthracycline and taxane regimen. In principle, and because of other studies that we did not detail, a sequential regimen is better than a combination regimen; there is no benefit in adding another drug, so there were studies evaluating the addition of capecitabine or gemcitabine, there was no benefit, and there is also no benefit in extending the number of cycles. Therefore, that’s the recommendation for the clinical practice.

What are some of the surgical challenges involved?

One of the most important prognostic factors and also a factor very important for treatment decisions is the axillary status. It is a challenge, sometimes, to perform a correct staging of the axilla before starting the neoadjuvant treatment since we are now performing the surgical approach. There are some discussions on what are the best imaging techniques to use; the availability of MRI has made our life easier in the countries where people can have access to this imaging technique and also it is extremely important that if, either clinically or in an ultrasound or mammography or MRI, there is the detection of a suspicious lymph node, there has to be a biopsy or at least a fine needle aspiration to confirm the positivity or not of these lymph nodes. This is quite important to decide if chemotherapy is necessary and what type of chemotherapy, particularly in ER positive disease, if we need to go for six or eight cycles or if four cycles will be enough.

Another challenge is the type of treatment or type of surgical approach after the neoadjuvant therapy. So in some situations the pre-neoadjuvant treatment decision would be a mastectomy; if there is a very good response, be it a pathological complete response or not, we can perform safely a breast conserving surgery. Also in this ESMO conference there was a presentation of one of these neoadjuvant studies, the Neo-ALTO study showing that, despite the fact that there were high rates of response, the percentage of mastectomies was still very high. There’s an analysis of why would that be happening and there are several reasons for that, one of them might be the pre-treatment decision of the surgeon that a mastectomy was necessary. So there is still a lot of work to be done in deciding what is the best surgical approach after neoadjuvant therapy for the breast but also, for example, if the sentinel lymph node biopsy is a safe technique to perform after neoadjuvant therapy or if it should be done before.

Nevertheless, in all these discussions that we had during the educational session, there was one main message and that message is that the PCR rate is a very strong prognostic factor. This is true for all the subtypes, even for the triple negative. If a triple negative breast cancer patient achieves a PCR after neoadjuvant therapy, the outcome is quite good. It is very dismal if the tumour does not achieve a PCR, but in a non-triple negative excluding the luminal As, in a non-triple negative if there is no PCR the long-term outcome is also dismal and important new therapies must be developed for these patients.