The Women's Health Initiative randomized trial of calcium plus vitamin D: Effects on breast cancer and arthralgias.

Reviewer: John P. Plastaras, MD, PhD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 6, 2006

Presenter: R. T. Chlebowski
Presenter's Affiliation: Los Angeles Biomedical Research Institute, Torrance, CA
Type of Session: Plenary

Background

In 12 of 16 retrospective observational studies, calcium (Ca) and vitamin D (D) have been associated with reduced breast cancer risk, decreased breast density, and decreased arthralgias
Question: Would prospective Ca and D supplementation decrease risk of breast cancer?

Materials and Methods

Double-blind, placebo-controlled study of 32,282 women randomized to:
- Ca/D arm (n=18,176): 1000 mg Ca as calcium carbonate + 400 IU vitamin D3
- Placebo arm (n = 18,106)
The Ca/D study was part of a larger study that included patients on two other studies:
- a dietary modification intervention studyHormone therapy vs. placebo (54% of these patients)
  - conjugated equine estrogen + medroxyprogesterone (or estrogen alone for those with hysterectomy)
Criteria:
- post-menopausal, life expectancy > 3 yr, no breast cancer in last 10 yr
- excluded hypercalcemia, kidney stones, corticosteroid use
Endpoints:
- Primary: Hip fractures
- Secondary: Invasive breast cancer incidence, Colorectal cancer
Allowed personal use of Vit D supplementation
- Initially 600 IU, subsequently increased to 1000 IU
- Serum vit D levels were measured in a subset of participants

Results

Groups were well balanced, including baseline Ca and D intake, Gail risk
Semi-annual contact to assess adherence
- 60-63% in first year
Terminated after 7 yr
There was no difference in invasive breast cancer incidence
- 528 Ca/D vs. 546 placebo
- HR 0.96 (95% CI 0.85-1.09)
- No difference in non-invasive breast cancers either
Subgroups analyses revealed a possible benefit from Ca/D to lower invasive breast cancer risk
- Adherence-adjusted favored Ca/D (HR=0.91, p=0.09)
- Subgroup not taking supplement at baseline (HR=0.82, p=0.008)
Invasive breast cancers were smaller in Ca/D arm
- 1.54 +/- 1.23 cm Ca/D vs. 1.71 +/- 1.29 cm placebo (p=0.05)
Total vit D baseline intake was associated with lower breast cancer risk in the placebo group
Baseline vit D deficiency was common as measured in serum
- Not correlated with joint pain symptoms
Joint symptoms did correlate with hormone therapy (p<0.01), but did not differ between Ca/D and placebo arms
Kidney stones were more frequent in Ca/D arm

Author's Conclusions

Supplementation with Ca/D did not decrease incidence of breast cancer, but tumors were somewhat smaller
Ca/D did not decrease joint pain symptoms

Clinical/Scientific Implications

Although retrospective studies and pre-clinical data would predict that Ca/D could lower breast cancer incidence, supplementation as used in this study did not confer a benefit
Possible explanations for the lack of effect on breast cancer incidence:
- Too much baseline Vit D use (~750 IU) compared with level of intervention (400 IU) to see an effect from intervention
- Not enough Vit D intervention? Need about 3000 IU to achieve serum level of 42 ng/mL, which has been correlated with greatest breast cancer risk decrease
- Too much baseline Ca use (mean intake was 1165 mg, which is close to optimal amount, 1200 mg)
- Participation in hormone therapy trial may have confounded effect
- Intervention in the right age group?
At the present time, Ca and Vit D supplementation can not be recommended to prevent breast cancer