Abstract C28: Effects of vitamin D supplementation on breast imaging and blood-based biomarkers of breast cancer risk
Authors: Sivasubramanian Parijatham S. , Xiao Tong , Hershman Dawn L. , Maurer Matthew , Kalinsky Kevin , Feldman Sheldon , Brafman Lois , Refice Susan , Kranwinkel Grace , Crew Katherine D. 
Published: May 2019

Abstract
Background: Vitamin D deficiency is a potentially modifiable risk factor that may be targeted for breast cancer prevention. Observational studies have demonstrated an inverse association between breast cancer and vitamin D status, including the main circulating form of serum 25-hydroxyvitamin D [25(OH)D]. The relationship between vitamin D and mammographic density (MD), a strong predictor of breast cancer risk, remains unclear. Despite a number of clinical trials of vitamin D supplementation, the efficacy, optimal dose of vitamin D, and target level of serum 25(OH)D for breast cancer prevention remain unclear. We examined the effects of high-dose vitamin D on breast imaging and circulating biomarkers among women at high risk for breast cancer.
Methods: Forty high-risk women [defined as a 5-year breast cancer risk per the Gail model of ≥1.67%, lobular or ductal carcinoma in situ (LCIS/DCIS)] were assigned to a 1-year intervention of vitamin D3 20,000 IU or 30,000 IU weekly. Other eligibility criteria included baseline MD ≥25%, serum 25(OH)D ≥32 ng/ml, no current tamoxifen or raloxifene use, and no history of kidney stones. Women underwent a digital mammogram at baseline and 12 months, and serial blood draws at baseline, 6 and 12 months. In addition, postmenopausal women underwent a breast MRI at baseline and 12 months. Participants were monitored for toxicity during follow-up visits every 3 months. Biomarker endpoints included changes in breast density by mammography and breast MRI, serum 25(OH)D, 1,25(OH)D , PTH , IGF-1 , IGFBP-3. MD was evaluated by the Cumulus technique and fibroglandular tissue volume was measured using a novel segmentation method on noncontrast T1-weighted images from breast MRIs. Paired t-tests were used to compare biomarker changes from baseline to follow-up. Multivariate linear regression was used to determine the association between breast density and blood biomarkers with adjustment for known confounders.
Results: From Nov 2007 to Jan 2011, 40 women were enrolled. Median age 50 years (range, 37-73); pre/postmenopausal: 20/20; Non-Hispanic white/Hispanic/Non-Hispanic black/Asian: 18/20/1/1; median body mass index (BMI) 26.6 kg/m2 (20-39.6); elevated Gail risk/LCIS/DCIS: 20/10/10; baseline serum 25(OH)D 19.9 ng/ml (9.4-30.4); baseline MD 14.5% (0.9-60.4). At baseline, 6 and 12 months, mean serum 25(OH)D rose from 20.0 to 43.8 to 46.8 ng/ml, respectively; and mean serum 1,25(OH)D increased from 69.7 to 86.8 to 98.1 pg/ml, respectively (p&lt;0.01). Compared to baseline, serum PTH decreased significantly at 6 months (35.0 vs. 29.2 pg/ml, p&lt;0.01) and IGF-1/IGFBP-3 ratio decreased at 12 months (0.0341 vs. 0.0327, p=0.01). After 1 year of high-dose vitamin D, there was no significant change in MD (19.2% vs. 20.8%, p=0.54), regardless of menopausal status or dose level. In univariate analysis, serum 25(OH)D was inversely correlated with MD at 12 months (p=0.02), however, the association was no longer significant after adjustment for age, race, BMI, and menopausal status.
Discussion: We demonstrated that a 1-year intervention of high-dose vitamin D3 was associated with a significant increase in serum 25(OH)D above a target level of 40 ng/ml. Previous studies have shown a direct association with IGF-1/IGFBP-3 ratio and breast cancer risk. We found a decrease in serum IGF-1/IGFBP-3 ratio with vitamin D supplementation. However, no significant change in MD was noted. Analysis of breast MRI fibroglandular tissue volume is ongoing in a subset of postmenopausal women. These early phase chemoprevention trials are designed to enhance our understanding of the biologic effects of vitamin D on intermediate biomarkers of breast cancer risk.
Citation Format: Parijatham S. Sivasubramanian, Tong Xiao, Dawn L. Hershman, Matthew Maurer, Kevin Kalinsky, Sheldon Feldman, Sr., Lois Brafman, Susan Refice, Grace Kranwinkel, Katherine D. Crew. Effects of vitamin D supplementation on breast imaging and blood-based biomarkers of breast cancer risk. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C28.