Abstract P1-09-02: Pilot study of a 1-year intervention of high-dose vitamin D in women at high risk for breast cancer.
Authors: Sivasubramanian PS , Hershman DL , Maurer M , Kalinsky K , Feldman S , Brafman L , Refice S , Kranwinkle G , Crew KD 
Published: August 2014

Abstract
Background: Selective estrogen receptor modulators (SERMs) have been shown to decrease breast cancer incidence among high-risk women, but uptake for prevention has been poor. Observational studies have demonstrated that serum 25-hydroxyvitamin D (25-OHD) is inversely related to breast cancer risk, such that levels &gt;40 ng/ml are associated with about a 40% reduction in breast cancer risk compared to women who are vitamin D deficient (25-OHD &lt;20 ng/ml). 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 women at high risk for breast cancer.
Methods: Forty high-risk women (defined as a 5-year Gail risk ³1.67%, lobular or ductal carcinoma in situ [LCIS/DCIS], BRCA1/BRCA2 mutation carrier, or stage I/II invasive breast cancer in remission for &gt;5 years) were assigned to a 1-year intervention of vitamin D3 20,000 or 30,000 IU weekly. Other eligibility criteria included baseline mammographic density (MD) ≥25%, serum 25-OHD ≤32 ng/ml, no current SERM use and no history of kidney stones. Women underwent a digital mammogram at baseline and 12 months, and serial blood draws every 3 months. In addition, random core breast biopsies were conducted in premenopausal women, whereas postmenopausal women underwent a breast MRI at baseline and 12 months. Participants were monitored for toxicity, particularly hypercalcemia and hypercalciuria, every 3 months. The primary objective is to determine the safety and feasibility of high-dose vitamin D in this study population. Secondary objectives are to determine changes in breast density and blood-based biomarkers (25-OHD, 1,25(OH)D, PTH, IGF-I, IGFBP-3). Serum 25-OHD was measured by Diasorin radioimmunoassay.
Results: From November 2007 to January 2011, 292 women were screened and 142 were ineligible. Main reasons for ineligibility (%) included 25-OHD &gt;32 ng/ml (27), opted for SERM (23), prior kidney stones (11), and MD &lt;25% (9). Of the 40 enrolled participants: median age 50 years (range, 37–73); pre/postmenopausal: 20/20; white/hispanic/black/asian: 19/14/6/1; median body mass index 26.6 kg/m2 (20–39.6); elevated Gail risk/LCIS/DCIS/stage I or II breast cancer: 20/10/8/2; mean baseline serum 25-OHD 20.2 ng/ml (9–31). Currently, 1 participant is on-study, 31 completed the intervention, 6 were lost to follow-up, 1 withdrew due to hypercalciuria (spot urine Ca/Cr &gt;0.37) and 1 withdrew due to dyspepsia. Mean serum 25-OHD rose to 47 ng/ml at 3 months, 49.1 ng/ml at 6 months, and 53.7 ng/ml (range, 26–77) at 12 months. No significant hypercalcemia (serum Ca &gt;10.5 mg/dl) occurred at either dose level. Imaging and biomarker analyses are ongoing.
Discussion: We have demonstrated that a 1-year intervention of high-dose vitamin D3 is well tolerated and can increase serum 25-OHD above a target level of 40 ng/ml. This preliminary data has informed an ongoing phase IIb randomized placebo-controlled trial (SWOG 0812) of high-dose vitamin D in 200 high-risk premenopausal women and highlights the importance of early phase breast cancer chemoprevention trials with intermediate biomarker endpoints to test novel agents.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-09-02.