SABCS 2012: The Azure Trial – Vitamin D, Zoledronic Acid, and Thoughts on Menopause

By Karuna Jaggar, Executive Director

Advocates have been calling out for many years for studies of non-toxic and complementary therapies. Ann Fonfa, founder of the Annie Appleseed Project made several public pleas at this year’s conference.

The closest thing we saw this year was the AZURE trial, which, although not the primary focus of the study, found that Vitamin D levels were correlated with relapse of early breast cancer.

The study included 3,360 women with Stage II and Stage III disease. Women were randomized to standard therapy or standard therapy plus zoledronic acid (a bisphosphonate marketed under trade names such as Zometa, Reclast) for 5 years. All patients received Calcium and Vitamin D supplements for 6 months and thereafter at the discretion of the physician.

The data on zolodronic acid was presented last year and there was no difference between the control and treated arms. However a planned subgroup analysis found some benefit for menopausal women (whether natural or induced) in the treatment arm who had slightly better overall survival and disease free survival.

The research presented this year aims to explain that study result by identifying ways of knowing who is more likely to experience bone metastasis, markers for who might benefit from zoledronic acid, and classify menopausal status using reproductive hormones rather than the presence of a period.

The researchers found that Vitamin D levels, rather than bone turnover, were predictive of metastasis. AZURE was a UK study and the researcher noted that just 10% of the population in the UK have sufficient levels of Vitamin D at the time of diagnosis. [With my British ancestry, I couldn’t help note that there are several sources of Vitamin D, of which sunshine is one—and of course Britain is legendary for it’s lack of sun.] The relatively few women with sufficient levels of Vitamin D appear to have much better prognosis.

The problem is that we don’t really know what “low” and “adequate” levels of Vitamin D are—if you change the cut off, you can influence what percent of the population is low, etc. There was comment that the study started in 2003 and speculation that the recommendation at the time of 400 IUs of Vitamin D is now probably not sufficient. And we have seen other studies where large doses of vitamin supplements have harmful results.

Nor are there immediate clinical lessons or ways of applying these findings. We don’t know if the form of Vitamin D makes a difference—is a supplement (vitamin pill) as good as sunlight, food, etc.? Furthermore, what about threshold and timing?

This is a hypothesis generating study and does not establish a true causal relationship nor a way to address the issue. Fundamentally, we don’t know anything about the mechanism linking Vitamin D to breast cancer even with this data from AZURE. It joins a small number of studies and some lab data that suggests breast cancer is worse in a low vitamin D environment. We don’t know if it’s the Vitamin D itself or if it’s a reflection of something else that is important. And most importantly of all, we don’t have data to suggest that replacing Vitamin D will change outcome.

One final note on the AZURE trial is that it’s difficult to compare clinical menopause to biochemical menopause because menopause is not predictable or stepwise and it takes several years. This means that physical symptoms of menopause do not always match levels of reproductive hormones associated with menopause. As Dr. Hope Rugo of UCSF said, commenting on the trial, the only true way to know if a woman is not menopausal is if she is having periods, but the absence of periods is not at all clearly the indicator of true menopause.

So, once again, this study gives us much intriguing information but mainly points out how much we still don’t know and need to learn before making any definitive conclusions.

This entry was posted in BCA News.