2013 San Antonio Breast Cancer Symposium (SABCS)
Long term use of aromatase inhibitors and compliance
Prof Peter Barrett-Lee - Cardiff University, UK
This morning was very interesting and it mainly focussed on oestrogen receptor positive breast cancer and there were two main types of presentation. There was work on preventing breast cancer using anti-oestrogens such as anastrozole but they cause, in some women, unacceptable side effects including joint pains which we call arthralgia. So there was work from Jack Cuzick that we saw presented that showed actually even in the placebo group, so the group of women who were having placebo, they had quite high levels of joint pains, more than half. So it tells us something that actually what we’re seeing when we deal with breast cancer patients every day who have arthralgia, it may not all be due to the aromatase inhibition, there might be quite a big background, actually, in this age group of joint pains which I guess we all perhaps recognise to some extent as we get older. But perhaps we’d underestimated the extent of that.
The next presentation straight after his was looking at what we might do about it and it was actually on exercise, a randomised trial of exercise. So patients on aromatase inhibitors with joint stiffness and arthralgia were randomised to have a special exercise programme or just their normal advice. There was about a 30% reduction in pain, particularly pain was the main effect of the exercise. Again there’s a message there saying that you can ignore these joint pains, they’re not telling you to stay still, they’re actually better if you keep moving and that’s a positive message anyway for health. So we can now help women a bit more to understand what they’re going through, that it’s not all due to the aromatase inhibitor.
There was another presentation which I think was very pertinent to some countries in the world was the work looking at how much it costs you to get your drug and whether you are compliant with taking it. That was from the US group looking at the patients who were offered generic substitutes for anastrozole, so the generic form which is much cheaper and the compliance was much higher. So it’s quite a worry for health systems where you have to pay quite huge amounts for your medication. Evidence there that many patients just can’t afford it and don’t buy the drug.
Why is there such a problem with compliance for aromatase inhibitors?
It’s interesting; as you know, I’ve been talking with Jack Cuzick about this and I think it’s interesting. They seem to have got themselves quite a bad name for causing arthralgia. The original trials where anastrozole was compared with Tamoxifen did show that actually around about 40% of all patients had arthralgia as a side effect, it wasn’t just the aromatase inhibitor. But there’s become this perception now that aromatase inhibitors are worse at doing that than Tamoxifen and that they make lives unacceptable in some cases. There was a very passionate speech by one of the patient advocates in the question section saying, look, we need to talk to these women, we need to explain as much as we can about how we can help them because compliance is so important because otherwise they run the risk of dying of breast cancer and that’s a tragedy. If it’s either because they can’t afford the drug, that’s obviously a scandal, or if it’s because we’re not explaining how important the treatment is, but also helping them to overcome the side effects. I think the trial was called HOPE, which is quite a good name for the exercise trial.
We then switched into mechanisms of resistance in established breast cancer and actually there was a resurgence of an old story which is that are there mutations in the oestrogen receptor, particularly the oestrogen receptor 1? It was previously thought that it wasn’t a big issue because several series 10-15 years ago looked at primary tumours and found very low levels of mutation in the oestrogen receptor, less than 1%. So it was thought that this is not a story to explain what we’re seeing in the clinic, which is resistance. However, two groups now have looked at metastatic samples, so not the primary tumours, sometimes primary tumours, but also comparing them with the metastatic tumours and particularly tumours from patients’ metastases but where they have undergone hormone therapy, several lines, and are resistant to it. What they found was a much higher level, perhaps as high as 14-15%, had aberrations in the oestrogen receptor, either mutations, sometimes amplification even and one case of translocation with another piece of DNA. So what that’s telling us is that there clearly is some kind of progression and genomic instability as we go through resistance. So that story is back on again; we can now think about what are those genetic changes in the oestrogen receptor, how are they causing resistance, what are the mechanisms and then target them. So I think that’s really important because we may have been missing that whole chunk of cause for resistance previously.
Finally we had a fantastic talk from Mike Stratton from the Sanger Institute about mutations in breast cancers and trying to group them according to signatures. This is really only possible with these new high throughput sequencing systems that we have now and we can sequence thousands and thousands of tumours from patients. What we’re seeing emerge is a pattern of perhaps more than 25 types of signature where there are mutations in parts of the breast cancer genome and they can be grouped into about 25 or more types of signature. Some of those are associated with oestrogen receptor negative breast cancer and there’s a thinking that the pattern may reflect some kind of inflammation changes, perhaps earlier in life. So we’re seeing a result of the battle, perhaps 20-30 years earlier which was successfully won, perhaps over a virus, but then led to side collateral damage on DNA which set up these cells to become malignant 20-30 years later. So, a really great talk and a good one to finish the morning on and quite positive really.