European Multidisciplinary Cancer Congress (EMCC) 2011, 23-27 September, Stockholm

Zoledronic acid reduces recurrence of breast cancer

Professor Robert Coleman – Weston Park Hospital, Sheffield, UK

 

Good morning ladies and gentlemen, thank you very much for coming so early and giving me the opportunity to summarise what I think is a very interesting study, the AZURE trial which will be presented later today and is published in the New England Journal of Medicine tomorrow.

This is a trial, an academic trial, run from the United Kingdom but with important contributions from other countries, looking at whether a bisphosphonate, zoledronic acid, which we already use for patients with metastatic bone disease and the treatment of osteoporosis, could modify the course of early breast cancer and delay or prevent metastasis and recurrence.

As you can see it was a large trial, 3,360 women and all these patients had what we call early breast cancer, so this is disease confined to the breast and axillary lymph nodes. You can see where the patients came from in the bottom left of that slide and it was a very simple, pragmatic design in that patients were randomised between standard adjuvant therapy, so whatever chemotherapy, hormone therapy, radiotherapy was appropriate they had, and on top of that they either had zoledronic acid given in a schedule which persisted for five years, as you can see in the slide, or they were allocated to a control group. This was not placebo controlled because zoledronic acid is given as an intravenous infusion and that was felt to be an unreasonable imposition to give placebo infusions for five years.

The primary aim of this study was disease free survival, so that’s recurrence or death from some other cause, and the study took essentially all comers, so young and old, hormone sensitive and hormone insensitive and differs in that respect from other reports, other indeed positive reports, of this approach in either hormone sensitive postmenopausal women or hormone sensitive young women who have been pushed into a menopause with goserelin. We’ll come back to that important issue about menopause later.

From the primary endpoint this at first sight looks to be a disappointing study because when you take all patients there was no difference in disease free survival whether defined as in the primary endpoint or a more sophisticated endpoint called invasive disease free survival. Really no difference there and that overall result is unlikely to change so this is not a treatment for every woman with breast cancer. But we had planned at the outset to look at certain features that might identify who would and who would not benefit from this approach. Our hypothesis was that this treatment might be more relevant for patients with what we call high bone turnover, and the patients with high bone turnover are those that have gone through menopause. It might also be related to whether the tumour was hormone sensitive or insensitive. We looked at other aspects as well and the only important subgroup difference was indeed this one related to the menopausal status of the woman. So if, at the time of diagnosis, she had clearly gone through menopause, and we define that as more than five years since the last period, then there was a clear benefit to this treatment. So we call that a low oestrogen environment and there was a significant improvement in disease free survival.

On the other hand, in the younger patients who were still menstruating at the time they developed their breast cancer, or at least during the early follow-up phase, there is no benefit. This is shown in a bit more conventional way in these survival curves. On the left you have the disease free survival at the top and the overall survival for the younger patients, as I said before, no difference. But on the right you have the one-third of patients in this study that had clearly postmenopausal features at the time their diagnosis was made and here we see a significant improvement in disease free survival, with a hazard ratio of 0.75, so 25% reduction in recurrence and this has already translated into an improved overall survival with a hazard ratio of 0.74, so, again, about a 25% reduction in the risk of dying in this subset of patients.

This is a very busy slide, I don’t want you to worry about the details, but it’s an attempt to try and see what is going on here because this is a strange result. Zoledronic acid is meant to affect bone and in the top we’re looking at the effect of zoledronic acid on bone recurrence. It does what it says on the tin, it’s just not very good at it. It does reduce bone recurrence a little bit but not significantly and that is unaffected by age.

But the most remarkable result about this study is that what happens outside the bone. In older women there is a marked reduction in spread to other organs or back to the breast, whereas in the younger patients there appears to be an adverse effect of this treatment approach. The difference between those two groups is highly, highly significant, there’s only a 1 in 5,000 chance that that is a fluke result. So it’s possible, but it would seem unlikely.

So, to conclude, in terms of the primary endpoint, adjuvant use of zoledronic acid in this large trial did not improve disease free survival, so it is not a treatment for every woman with breast cancer, far from it. But what we have discovered is highly significant heterogeneity of affect by menopausal status, in other words, older patients appear to be benefitting, younger patients are not and possibly could be harmed. This is being driven by the spread of disease outside the bone, which we did not really anticipate when the study was set up. So adjuvant bisphosphonate efficacy and harm may be dependent on effects of the reproductive hormones, oestrogen and other hormones that are important in maintaining bone health and which change around the time of the menopause.

I suppose the bottom line is this is a subgroup analysis so when, if ever, should subgroup analyses influence clinical management, and that’s something the academic community are clearly going to debate over the coming months and years. Thank you very much.