SAN ANTONIO—Researchers in the AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial reported an unexpected finding here at the CTRC-AACR San Antonio Breast Cancer Symposium: Patients with high baseline levels of vitamin D had a better prognosis, with a lower risk for bone relapse (Abstract S6-4).
And among postmenopausal women, high levels of vitamin D also predicted improved outcomes for treatment with the bisphosphonate zoledronic acid.
The randomized Phase III trial of 3,360 women with stage II/III breast cancer showed that the bisphosphonate zoledronic acid had no effect on the recurrence of breast cancer or on overallsurvival at five years of follow-up (NEJM 2011;365:1396-1405).
A subset analysis did show an effect on both recurrence and survival in postmenopausal women with established menopause of five years or more since their last menstrual period.
At this meeting, AZURE lead author Robert E. Coleman, MD, Professor of the Cancer Clinical Trials Centre of the University of Sheffield, UK, reported on a subsequent analysis that showed that high pre-treatment serum levels of 25-hydroxyvitamin D are associated with lower risk of bone relapse, with a trend toward lower risk for any distant relapse.
Two other markers of bone turnover tested, N-terminal propeptide type I procollagen (P1NP) and beta C-terminal telopeptide type I collagen (βCTX), failed to significantly differentiate breast cancer patients who may be at high risk for distant relapse.
“Our results suggest that baseline bone turnover is not directly associated with the benefits of zoledronic acid among postmenopausal women,” he said. “And there is no convincing evidence that the treatment benefits observed in postmenopausal women in AZURE are associated with an increased rate of bone turnover.”
Interestingly, the researchers found that 90 percent of study patients had insufficient vitamin D levels at diagnosis. An insufficient level was 30 ng/ml or less.
But those patients who did have sufficient baseline vitamin D levels had a much better prognosis in terms of bone recurrence, with a hazard ratio of 0.11, Coleman said. “The number of [bone recurrence] events was relatively small, but they did reach statistical significance, and the effects persisted after adjusting for seasonal variation.”
There was also a trend toward improved prognosis in time to distant recurrence for patients with adequate vitamin D levels at diagnosis, with a hazard ratio of 0.56, but that was not statistically significant, he said.
All study patients received 400 IU of vitamin D before treatment, but Coleman said this would not be enough to bring up low levels.
For reference, session moderator Suzanne Fuqua, PhD, Professor of Medicine at Baylor College of Medicine, said that the Endocrine Society recommends 4,000 to 5,000 IU for adults and 1,000 IU for children.
Push for More Research
Steven E. Vogl, MD, a medical oncologist in the Bronx, NY, and astute observer at this and many other oncology meetings, commented from the audience: “There is accumulating evidence that ladies with low levels of 25 hydroxyvitamin D do worse. It is time for the advocates in this room to get together and push us to do a study of giving vitamin D to those women with low levels to an amount that gets them to a sufficient level, and see if that improves prognosis with a randomized, prospective trial.
“The technology is trivial, and the drug is cheap.”
Coleman said Vogl made a very good point: “We as oncologists are not well trained on how to replace vitamin D, and many of the formulations needed are not easy to access. But you are absolutely right—we should be measuring vitamin D, and replenishing it appropriately.”
Caution about Clinical Implications of Supplementation
A caution about the clinical implications of supplementation was offered from the audience by Rowan T. Chlebowski, MD, PhD, Professor in Residence at the David Geffen School of Medicine and Chief of Oncology/Hematology at Harbor-UCLA Medical Center: “In analyses in the Women's Health Initiative and other studies, only 20 percent of the difference between individuals in vitamin D levels is explained by diet, supplements, sunlight exposure, exercise, and body mass index. Probably 80 percent is genetically determined,” said Chlebowski, who led several studies from the Women's Health Initiative.
He added that aside from rickets, there are no known interventions where deficient vitamin D levels are supplemented that show a changing of outcome.