2010 San Antonio Breast Cancer Symposium, 8-12th December, USA
Interview with Dr Leif Ellisen (Massachusetts General Hospital, Boston, USA)
Exemestane potential for hormone-receptor positive, early-stage breast cancer in the adjuvant setting
This was a very large trial that was aimed at asking a question regarding new hormonal therapy for breast cancer. So in the past ten years there has been a whole new wave of breast cancer therapy involving new hormone therapy agents called aromatase inhibitors. There are several different aromatase inhibitors that are molecularly slightly different and there were predictions about whether they would have different side effect profiles and whether one aromatase inhibitor might be better than another aromatase inhibitor. This trial, which we called MA17, was a very large trial aimed to definitively ask this question about whether one aromatase inhibitor was better than another one. The new one that was tried was called Exemestane and it was tried against one that had shown to be very effective called Letrozole.
What was discovered?
We found out that in fact they seem to be equally beneficial for patients and that indeed the side effect profile of the two medicines was really quite similar. This was possibly what some people expected because we knew that these medicines fundamentally worked in the same way in terms of blocking oestrogen and the whole way that these agents prevent breast cancer recurrence is by starving the breast cancer cells of oestrogen. We knew that both of these drugs were very good at doing that, but because they work in slightly different ways it was thought that perhaps one would be better than another. But in fact this trial with a large number of patients with many years of follow-up for these patients really shows quite clearly that these drugs are equally beneficial for patients.
What sort of side effects did you see?
Most of the side effects of these medicines are the ones that we expect, given the fact that what these medicines really do is lower the oestrogen levels in the blood stream. We know that some of the things that oestrogen is important for is for preventing bone fractures, it’s for bone health, and also for cholesterol profiles and cardiovascular health. So one of the questions in these trials was: is there a significant risk of increased fractures or increased cardiovascular events? It’s slightly controversial how to interpret the studies, particularly with regards to the bone because if you compare an aromatase inhibitor, either of these agents – Letrozole or Exemestane, to what had been the standard therapy, Tamoxifen, usually you see more fractures but in fact what that may reflect is the fact that Tamoxifen, because in many tissues like the bone it functions as a pro-oestrogen, Tamoxifen actually is a bone strengthening agent. So the fact that there were more fractures in women, although the fractures are very small, we’re talking about a couple in a hundred, hundreds of patients treated, although the risk is very small it is elevated but that may be simply the fact that when you compare it to Tamoxifen, Tamoxifen protects against fractures and not necessarily indicating that these drugs like Exemestane actually increase fractures.
So there’s further research to be done?
Further research to be done and looking at larger patient numbers over long periods of time to really know whether these agents pose a significant risk. The same thing is true for cholesterol and for cardiovascular events such as heart attacks, we see very few heart attacks in any of these studies and so it’s clear that they are not going to be major contributors. But on the other hand they are going to become widely used for more and more women because they are such effective agents in breast cancer so we want to be sure that they’re as safe as possible and that we know about all the side effects, even if they might be very rare ones.
You’re also carrying out research into circulating tumour cells?
Circulating tumour cells are an incredibly exciting area in cancer biology. Initially it was thought that they might be most useful for simply monitoring the number of circulating tumour cells in the blood and the idea was that it might be a way to ask if a patient is really likely to relapse from their cancer. So if you had a cancer, the question is how likely is it to relapse, what do you need to do to prevent relapse? So we try to find every way we can to know whether in fact the patient is at high risk of having metastatic disease, which in most cases is incurable.
So one idea was if you count circulating tumour cells, that might give you a better indication than, for example, simply looking at the tumour itself. It turns out that some studies presented here at the meeting this week have suggested that that is indeed the case – that counting the number of circulating tumour cells might be helpful in addition to all the other things we look at in order to predict the patient’s prognosis, that is the risk that they will eventually relapse and develop metastatic disease.
What’s even more exciting for many of us though, and this goes to the heart of some of the research that we’re doing at Mass General Hospital, is all of the different ways that circulating tumour cells can be used. One example is a new discovery that patients who have breast cancers which are HER2 positive can be treated with targeted therapies such as Trastuzumab, but patients who are not HER2 positive tend not to benefit. What we’re finding, however, is that there are some patients whose tumours, we look at this HER2 in the tumour, some patients whose tumours are HER2 negative, their circulating tumour cells might actually be HER2 positive. Since we believe these circulating tumour cells are the cells that might be most important for relapse in metastasis, it could be that those patients, even if the tumour is negative but the circulating tumours cells are HER2 positive, those patients might benefit from some of these very effective anti-HER2 therapies like Herceptin. There are now clinical trials testing that hypothesis about whether patients whose tumour cells that are circulating are HER2 positive can benefit from these sorts of drugs.
Another exciting area is in drug resistance, so when we treat patients with drugs, even with advanced disease, they often become resistant to the drugs and the issue is the sooner we can know whether the patient is going to become resistant, the earlier that we can intervene with a new and better therapy. What we’ve shown through a study at Mass General published in the New England Journal of Medicine is that in some cases, this was in lung cancer but the principle is probably true for many cancers, you can actually detect the resistant cells among the circulating tumour cells earlier than you can see that the tumour itself in the patient has started to grow.
So normally a patient would simply be followed by scanning the patient and asking the question - is the tumour starting to re-grow on a therapy? But indeed looking at the circulating tumour cells you might be able to predict before the tumour starts to grow and may harm the patient, you can predict the resistance and intervene with a new medicine.
So this would require constant monitoring of circulating tumour cell levels?
That’s really the beauty of circulating tumour cells as contrasted, for example, to biopsy the patient where often if you have disease in the liver or the lungs, putting a needle into those areas of the body certainly has its risks. On the other hand, circulating tumour cells are monitored through a simple blood test which we take on patients anyway, a simple blood draw, so that’s really one of the biggest and most appealing aspects of all the work that’s being done in circulating tumour cells.