Abstract P1-07-01: Safety of High-Dose Vitamin D Supplementation in Premenopausal Women at High Risk for Breast Cancer

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Abstract Background: Vitamin D has diverse biological effects on proliferation, differentiation, and apoptosis in multiple tissues, including the breast. Observational studies have demonstrated that serum 25-hydroxyvitamin D (25-OHD), an objective measure of vitamin D status, is inversely related to breast cancer risk, such that levels >40 ng/ml are associated with a 40% reduction in breast cancer risk compared to women who are vitamin D deficient (25-OHD <20 ng/ml). Serum 25-OHD above 32 ng/ml is thought to be sufficient for bone health and vitamin D toxicity occurs with levels above 150 ng/ml. However, uncertainty remains about whether vitamin D supplementation will reduce breast cancer risk, the optimal dose of vitamin D, and the target level of serum 25-OHD. We examined the safety of high dose vitamin D and the effects on serum 25-OHD in premenopausal women at high risk for breast cancer. Methods: Twenty high-risk premenopausal women (5-year Gail risk score ≥1.67%, history of LCIS or DCIS, BRCA1 or BRCA2 mutation carrier) were assigned to a 1-year intervention of cholecalciferol (vitamin D3) 30,000 IU weekly (cohort 1, N=10) or 20,000 IU weekly (cohort 2, N=8/10). Eligibility criteria included baseline serum 25-OHD ≥32 ng/ml and no history of kidney stones. Participants were monitored for toxicity, particularly hypercalcemia and hypercalciuria, every 3 months during the 1-year intervention. They underwent a digital mammogram and random core breast biopsy at baseline and 12 months, as well as serial blood collections at 0, 6, and 12 months. Serum 25-OHD was measured by Diasorin radioimmunoassay. Results: From November 2007 to March 2010, 18 of 20 participants were enrolled and 12 have completed the 1-year intervention (10 in cohort 1; 2 in cohort 2). Median age: 47 (37-52); White/Hispanic/Black: 8/9/1; Median body mass index: 27.7 kg/m2 (21.5-35.4); Elevated Gail risk/LCIS/DCIS: 11/6/1; Mean baseline serum 25-OHD: 19 ng/ml (11-27). Women assigned to a dose of 30,000 IU weekly (cohort 1) rose to a mean serum 25-OHD of 55 ng/ml (26-75) at 6 months and 59 ng/ml (49-71) at 12 months. The dose of 20,000IU weekly (cohort 2) resulted in a mean serum 25-OHD of 48 ng/ml (35-59) at 3 months and 50 ng/ml (42-63) at 6 months. No significant hypercalcemia (serum calcium >10.5 mg/dl) or hypercalciuria (spot urine calcium/creatinine >0.37) occurred at either dose level. One woman dropped out due to worsening gastroesophageal reflux symptoms. Biomarker analyses for samples collected from cohort 1 are ongoing. Discussion: We have demonstrated that a 1-year intervention of high-dose vitamin D3 20,000 IU or 30,000 IU weekly is well-tolerated and able to increase serum 25-OHD above 40 ng/ml in all participants, without any episodes of hypervitaminosis D. The effects of high-dose vitamin D on mammographic density, tissue and serum-based biomarkers of breast cancer risk are currently being evaluated. Large-scale randomized controlled trials are necessary to determine the safety, efficacy, optimal dose and duration of vitamin D supplementation for breast cancer chemoprevention. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-07-01.