The study from Dr Hurvitz was very interesting because there was the idea of using first line therapy in which you add another mode of treatment to trastuzumab. So you’re adding everolimus, which is an mTOR inhibitor, looking at a different pathway and possibly getting it doing a better job of treating patients with breast cancer, hormone receptor positive and negative, actually, in the mix. What did you make of that study? First of all, what did we hear?
We heard that adding everolimus to a regimen that includes trastuzumab, which blocks HER2, and a chemotherapy drug didn’t overall improve the outcome of the patients. I think there are several reasons for that. One is that there are other reasons why tumours are resistant to trastuzumab; one of those is that HER2 is accompanied by three other family members in this receptor family and several studies have shown now that if you don’t block all of those family members you’ll have resistance in some patients. We also have some data to suggest that mutations in the downstream signalling pathway in proteins like PI3 kinase, for instance, or loss of a tumour suppressor PTEN will cause resistance to trastuzumab. This study gave everolimus to all patients that had HER2 positive disease; if they had restricted it, and we’ll find this out from more data that they’re studying now, it may have worked in those that had a PI3 kinase mutation or a PTEN loss because in those patients trastuzumab is not very effective. So more remains, I wouldn’t conclude that everolimus is a bad drug in this situation, it may be that we just didn’t select the right patients in order to see a benefit.
That’s perhaps something for the future but meanwhile there’s quite an interesting signal that was just below the level of statistical significance for hormone receptor negative patients in progression free survival. What did you make of that signal? Should we make anything of it in this context?
Probably. I think it’s more or less a hypothesis generator at this point although one could come up with some reasons why the oestrogen receptor negative cohort might have done better with everolimus. That is that PTEN loss, that is loss of this tumour suppressor gene, is a little more frequent in oestrogen receptor negative HER2 positive tumours and maybe that’s why the drug had more effectiveness there. But it could be the play of chance and there are other reasons why ER negative tumours are different than ER positive tumours, many of us feel that they are two separate kinds of tumours and should be studied separately even though they all have amplification of HER2. But they’re clearly different tumours and I’m not surprised that there would be differential effects by receptor status.
So there could possibly be a benefit in using everolimus with hormone receptor negative women?
It’s possible. It needs more study but that’s certainly a possibility.
It might be hard to do the study now though?
Well not really… well, it would be hard to do the study because there are many other drugs available to treat HER2 positive patients now so finding the right patient population is going to be the challenge. What I would do is to try and figure out which patients did benefit in this study and then target a follow-up study in those particular patients.
But Dr Hurvitz was talking about adverse events and there were some deaths. That is a bit of a worry and she said the combination of paclitaxel and everolimus seemed to be quite harsh, unexpectedly so.
Yes, everolimus is not an easy drug to give and what she pointed out was a lot of these really adverse effects and deaths from patients on everolimus occurred very early when everolimus was first introduced into community practice and I think many physicians weren’t really adept at using it yet and weren’t aware, with personal experience, of some of these side effects. Those side effects now, if you did the study now since it’s been around for a couple of years, you would see many, many less of those side effects and hopefully no deaths. But it is a dangerous drug like many of our drugs used to treat cancer and one has to be knowledgeable and careful in their use.
So what’s your overall verdict on trying to reach an alternative pathway to get at this breast cancer?
We’re not there yet. We know a couple of things; we know that the oestrogen receptor can be a bypass mechanism for blocking HER2 so if you’ve got a tumour that’s positive for both oestrogen receptor and HER2, if you only block one of those driver pathways the tumour’s not going to do very well with the treatment, you have to block both. So, as she mentioned, they’re trying now to block both oestrogen receptor and HER2 and using everolimus to block mTOR might be the way to go. In that situation maybe you would see a benefit in the ER positive subgroup.