Abstract OT3-3-02: Phase IIB randomized double-blind placebo-controlled biomarker modulation study of high dose vitamin D in premenopausal women at high-risk for breast cancer: SWOG S0812
Authors: Crew KD , Lew DL , Hershman DL , Refice S , Anderson GL , Hortobagyi GN , Goodman GE , Brown PH 
Published: August 2014

Abstract
Background: Priorities in breast cancer chemoprevention include developing agents effective against estrogen receptor (ER)-negative breast cancer and validating intermediate biomarkers which correlate with breast cancer risk. Vitamin D is a fat-soluble vitamin which regulates calcium and bone homeostasis, but also has diverse biological effects relevant to breast carcinogenesis. The biologically active form of vitamin D [1,25(OH)D] interacts with the vitamin D receptor (VDR) to modulate cell proliferation, differentiation, apoptosis, and angiogenesis. Epidemiologic data suggests that serum 25(OH)D levels &gt;40-50 ng/ml are associated with a 40-50% reduction in breast cancer risk compared to women with vitamin D deficiency (&lt;20 ng/ml). Given the high prevalence of vitamin D deficiency in the general population, vitamin D3 3000-4000 IU daily would be required to raise 25(OH)D to this putative target level. The central hypothesis of this proposal is that high-dose vitamin D will modulate biomarkers of breast cancer risk.
Trial Design: This trial is a phase IIB, randomized, double-blind, placebo-controlled study of oral vitamin D3 (cholecalciferol) 20,000 IU (2 capsules) weekly for one year in 200 premenopausal women at high-risk for breast cancer. Both groups will be supplemented with a standard dose of vitamin D3 600 IU daily. Participants will undergo a mammogram and optional random core breast biopsy timed within 10 days after the start of their menstrual cycle at baseline and 1 year and blood collections at baseline, 6, and 12 months. Participants will be monitored for toxicity, particularly hypercalcemia and hypercalciuria, every 3 months during the 1-year intervention.
Main Eligibility Criteria: High-risk is defined as a 5-year Gail risk score ≥1.67% or lifetime risk ≥20%, history of atypical hyperplasia, lobular or ductal carcinoma in situ, germline mutations in BRCA1, BRCA2, p53, or PTEN, history of stage I-II breast cancer in remission for &gt;5 years, or baseline mammographic density &gt;50%. Other eligibility criteria include baseline serum 25(OH)D ≤32 ng/ml, normal serum calcium and urine calcium/creatinine ratio, and no history of kidney stones.
Specific Aims: The primary endpoint is change in mammographic density at 12 months compared to baseline between the vitamin D and placebo groups. Secondary exploratory endpoints include breast tissue-based biomarkers (Ki-67, cleaved caspase-3, ER, VDR, and 1α-hydroxylase) and blood-based biomarkers (25(OH)D, 1,25(OH)D, PTH, IGF-1, IGFBP-3, VDR polymorphisms).
Statistical Methods: Power calculations are based on a two-sample comparison of normal deviates, using a 2-sided, 0.05-level test. To be conservative, we assume that 15% will have missing breast density data at 12 months and a 2% difference in mammographic density between intervention and control at 12 months with a the standard deviation for each arm of 4%. With 200 women randomized, the study will have 90% power to detect this difference.
Target Accrual: 200. Sixty-seven patients accrued as of June 2013. Accrual completion expected December 2014.
Contact: Katherine Crew, Columbia University Medical Center, kd59@columbia.edu.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-3-02.