A Randomized Trial of Calcium Plus Vitamin D Supplementation and Risk of Ductal Carcinoma In Situ of the Breast

Abstract

Background: The effect of calcium plus vitamin D (CaD) supplementation on risk of ductal carcinoma in situ (DCIS) of the breast, a nonobligate precursor of invasive ductal carcinoma, is not well understood. In this secondary analysis, we examined this association in the Women's Health Initiative CaD trial over approximately 20 years of follow-up.

Methods: A total of 36 282 cancer-free postmenopausal women (50-79 years) were randomly assigned to daily (d) calcium (1000 mg) plus vitamin D (400 IU) supplementation or to a placebo. Personal supplementation with vitamin D (≤600 IU/d, subsequently raised to 1000 IU/d) and calcium (≤1000 mg/d) was allowed. The intervention phase (median = 7.1 years), was followed by a postintervention phase (additional 13.8 years), which included 86.0% of the surviving women. A total of 595 incident DCIS cases were ascertained. Hazard ratios (HRs) plus 95% confidence intervals (CIs) were calculated.

Results: The intervention group had a lower risk of DCIS throughout follow-up (HR = 0.82, 95% CI = 0.70 to 0.96) and during the postintervention phase (HR = 0.76, 95% CI = 0.61 to 0.94). The group that used CaD personal supplements in combination with the trial intervention had a lower risk of DCIS compared with the trial placebo group that did not use personal supplementation (HR = 0.72, 95% CI = 0.56 to 0.91).

Conclusions: CaD supplementation in postmenopausal women was associated with reduced risk of DCIS, raising the possibility that consistent use of these supplements might provide long-term benefits for the prevention of DCIS.

Figure 1.

Consort diagram of participants in the Women’s Health Initiative randomized trial of calcium plus vitamin D supplementation trial showing numbers included in the analysis. ^aCases ascertained between the enrollment in the Women’s Health Initiative study and the enrollment in the calcium plus vitamin D trial. ^bAmong women free of DCIS of the breast and invasive breast cancer. BC = invasive breast cancer; CaD = calcium plus vitamin D intervention arm; DCIS = ductal carcinoma in situ of the breast; DM = dietary modification; HT = hormone therapy.

Figure 2.

Kaplan-Meier estimates of cumulative hazards of ductal carcinoma in situ in the Women’s Health Initiative randomized trial of calcium plus vitamin D. Incidence rate per 1000 person-years was calculated at 5, 10, 15, 20, and 20 or more years of follow-up. All statistical tests were 2-sided. CaD = calcium plus vitamin D intervention arm.

Figure 3.

Kaplan-Meier estimates of cumulative hazards of ductal carcinoma in situ by trial arm assignment and reported personal use of calcium plus vitamin D supplements over time. Hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for age, race, body mass index, hormone therapy enrollment and randomization, dietary modification enrollment and randomization, years since menopause, physical activity, and Gail score for breast cancer risk. Incidence rate per 1000 person-years was calculated at 5, 10, 15, 20, and 20 or more years of follow-up.

Figure 4.

Hazard ratios (HR) for risk of ductal carcinoma in situ of the breast associated with supplemental calcium plus vitamin D (CaD) according to selected baseline characteristics. The error bars represent the 95% confidence intervals (CIs). The analyses were stratified by age, hormone therapy trial arm participation, dietary trial arm participation, and previous breast biopsy. The analyses were stratified by trial phase (time-dependent). Physical activity (metabolic equivalent-hours/week [MET-h/wk]) tertiles (tt) cutoffs: tt0 = 0; tt1 = 0.50-5.33; tt2 = 5.38-14.17; tt3 = 14.25-134.17. Gail model risk of breast cancer tertiles cutoffs: tt1 = 0.37-1.24; tt2 = 1.25-1.74; tt3 = 1.75-12.97. BMI = body mass index; CaD = calcium plus vitamin D; HRT = hormone replacement therapy.