SABCS 2012
The AZURE translational study
Professor Robert Coleman – Weston Park Hospital, University of Sheffield, UK
The AZURE trial, which is a large adjuvant early breast cancer trial of 3,300 women, which was designed to see if the bisphosphonate zoledronic acid could help prevent recurrence and spread of early breast cancer. We published these data last year showing that overall there wasn’t a benefit but in postmenopausal women we saw an improvement in disease free and overall survival.
So really what I was concentrating on today was to try and explore why this might be. Clearly older women have different hormone levels and they have different bone turnover rates with bone turnover generally being higher in older women than it is in younger women. We had a look at some serum samples that we had collected from patients before randomisation; we had samples from 870 women, all from the UK, and we measured a couple of bone markers which are well recognised as being appropriate, one called P1NP, one called Ctx and also vitamin D as a more general assessment of bone health and general health. I suppose expecting that higher bone turnover would be predictive of recurrence and might be predictive of benefit, but actually it wasn’t either. So having a high bone turnover didn’t mean you were more likely to get bone metastases or recurrence and it didn’t predict who was going to get benefit from zoledronic acid. However, interestingly, that wasn’t the same for vitamin D. Firstly most women in the UK have low levels of vitamin D and in fact in our population we only had 10% who had what would be called replete or sufficient levels. But if you did have normal levels of vitamin D you seemed to do a lot better, so your risk of getting a bone metastasis was much less, it was actually reduced by 90% which is almost too big a difference to be believable. But also for more distant and general recurrence there was almost a halving in recurrence rates in that group of patients. So that was interesting.
We then reclassified our patients’ menopausal status by measuring their hormone levels because for some women it’s obvious they’re premenopausal or postmenopausal but in those years around the menopause menopause isn’t complete or if a woman has had a hysterectomy she may not know exactly where she is around the menopause. So hormone measurements can give you some handle on that so we did that and segregated all the patients into either menopausal or not menopausal. Essentially what that showed was that using the hormone tests we still saw benefit in the postmenopausal population so it kind of validated our clinical observation and, of the hormone tests we did, estradiol rather than FSH or a third hormone called inhibin seemed to predict for a better outcome with women with low estradiol gaining benefit and those with estradiol above a certain threshold actually doing somewhat worse with this treatment.
So these are exploratory analyses, we still don’t understand the real mechanisms going on but perhaps a piece in the jigsaw of understanding this complex biology.
Has there been evidence showing vitamin D’s benefit?
The relationship between vitamin D and cancer is quite complex and growing in its understanding. Firstly, vitamin D levels may be related to the development of cancer in the first place with low vitamin D being a predictor of developing a number of cancers, breast cancer, colorectal cancer and possibly others. It’s also, I guess, a marker of ill health because it’s an indicator that diet is poor and getting out into the sunlight is less frequent. So what we don’t know is whether it’s acting directly as a stimulus to cancer or it’s just an indirect surrogate. Then when you’ve got cancer, certainly for breast cancer, there are a number of studies now that seem to suggest that those women with low levels of vitamin D do less well. Whether replacing vitamin D would reverse that, we don’t know. It’s quite difficult, even with replacement to get your vitamin D levels up if you’re the sort of person that naturally has quite low values. So it’s not an easy thing to assess.
Are there any on-going trials?
No, I’m not aware of any current studies, there are a number under discussion and interestingly it’s like a lot of old drugs, if you like, that are now being re-evaluated for their relevance in treating cancer, so aspirin, metformin, vitamin D. So we’ll be able to do some trials with some very cheap drugs soon.
