Study of Vitamin D for Premenopausal Women at High Risk for Breast Cancer - Full Text View

Sponsor:	Columbia University
Collaborator:	Prevent Cancer Foundation
Information provided by (Responsible Party):	Columbia University
ClinicalTrials.gov Identifier:	NCT00976339

Purpose

Despite significant advances in the early detection and treatment of breast cancer, it is still the most common cancer among women in the U.S. and up to 25% will die of their disease. Therefore, more attention has focused on primary prevention to reduce breast cancer-related morbidity and mortality. Due to the limited number of significant modifiable risk factors for breast cancer, researchers are exploring the potential of chemoprevention to arrest or reverse cancer development with a drug intervention. Currently, tamoxifen is the only FDA-approved drug for breast cancer risk reduction. However, tamoxifen's adverse effects have limited its usage. It is anticipated that raloxifene will be used more, as it has a more favorable side effect profile. However, tamoxifen and raloxifene do not prevent estrogen receptor (ER)-negative breast tumors, which account for about a third of all breast cancers and are associated with a poorer prognosis. Current priorities in breast cancer chemoprevention are to identify preventive agents which may be effective against ER-negative breast cancers, and have a low risk of side-effects.

Vitamin D is a fat-soluble vitamin which is produced in the body and may come from food sources. Epidemiologic studies suggest that vitamin D may influence breast cancer development, which has resulted in increased interest in the use of vitamin D for the treatment and prevention of breast cancer. Numerous experimental studies have shown that vitamin D compounds have anti-carcinogenic properties against breast cancer. Given the epidemiologic data and the extensive preclinical evidence of the anti-tumor effects of vitamin D, it is therefore reasonable to test the biological effects of high-dose vitamin D in early phase clinical trials. The investigators hypothesize that vitamin D3, cholecalciferol, will modulate biomarkers of breast cancer risk.

Condition	Intervention
Breast Cancer	Dietary Supplement: cholecalciferol (Vitamin D3)

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Prevention
Official Title:	Pilot Biomarker Modulation Study of Vitamin D in Premenopausal Women at High Risk for Breast Cancer

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer Vitamin D

Drug Information available for: Cholecalciferol

U.S. FDA Resources

Further study details as provided by Columbia University:

Primary Outcome Measures:

Safety and Feasibility [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Histologic changes, Mammographic Density, and Biological Correlates [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment:	20
Study Start Date:	September 2007
Estimated Study Completion Date:	June 2012
Primary Completion Date:	December 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Cohort 1 Cohort 1 to take 30,000 IU Vitamin D weekly for one year	Dietary Supplement: cholecalciferol (Vitamin D3) cholecalciferol (D3) 30,000 IU weekly for one year Other Name: Vitamin D
Experimental: Cohort 2 Cohort 2 to take 20,000 IU Vitamin D weekly for one year	Dietary Supplement: cholecalciferol (Vitamin D3) cholecalciferol (D3) 20,000 IU weekly for one year Other Name: Vitamin D

Detailed Description:

The investigators plan to conduct a pilot feasibility study in 20 premenopausal women who are at high risk for breast cancer development who will receive oral cholecalciferol (vitamin D3) 30,000 IU (n = 10) or 20,000 IU (n = 10) weekly for one year. Pretreatment and posttreatment mammograms, breast biopsies, and blood will be evaluated for a variety of biomarkers. The primary objective of this study is to determine the feasibility and toxicity associated with this 1-year intervention of vitamin D in this study population. The secondary objective is to obtain preliminary data on the biological effects of vitamin D on normal breast tissue. The results of this pilot study will be used to implement a larger multicenter trial of vitamin D for breast cancer chemoprevention.

Eligibility

Ages Eligible for Study:	21 Years and older
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Elevated risk of breast cancer defined as having at least one of the following: (1) Predicted 5-year modified Gail model risk of 1.7% or greater, (2) Lobular carcinoma in situ, (3) Known BRCA1 or BRCA2 deleterious mutation carrier, (4) Prior history of ductal carcinoma in situ, if no current tamoxifen use or prior radiation to the contralateral breast.
Age 21 years or older.
Premenopausal defined as < 6 months since the last menstrual period, no prior bilateral oophorectomy, not on estrogen replacement, and serum FSH values consistent with institutional normal values for the premenopausal state.
Normal breast exam and mammogram (BIRADS score of 1 or 2).
Baseline mammographic density ≥25% as assessed qualitatively by the mammographer (25-50% = "scattered fibroglandular densities"; >50-75% = "heterogeneously dense breasts"; >75% = "extremely dense breasts").
Baseline serum 25-hydroxyvitamin D <32 ng/ml.
Prior tamoxifen use is allowed provided treatment is discontinued at least 28 days prior to enrollment.
Willingness to allow submission of core needle breast biopsy for pathology review and collection of blood for biomarker analysis and banking.
At least one breast available for imaging and biopsy.
Willingness to not take calcium or vitamin D supplements during the one year intervention, due to the potential risk of hypercalcemia/hypercalciuria with high dose vitamin D. Premenopausal women who need to take calcium supplementation for any medical condition will be excluded from the study. Dietary restrictions on calcium intake may be imposed if the subject is found to have borderline high serum or urine levels of calcium during the study intervention and a list of dietary sources of calcium will be provided.
Normal serum calcium.
No history of kidney stones.
Adequate renal and hepatic function: serum creatinine, bilirubin, AST, ALT and alkaline phosphatase < 2.0 x the institutional upper limit of normal (IULN).
No hypersensitivity reactions to vitamin D.
Zubrod performance status of 0 or 1.
Not pregnant or nursing.
Agree to use effective contraception, hormone-based oral contraceptives allowed but switching birth control methods is discouraged while on-study.
No significant medical or psychiatric condition that would preclude study completion.

Exclusion Criteria:

Not meeting one or any of inclusion criteria

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00976339

Locations

United States, New York
Columbia University Medical Center Herbert Irving Cancer Center
New York, New York, United States, 10032

Sponsors and Collaborators

Columbia University

Prevent Cancer Foundation

Investigators

Principal Investigator:

Katherine Crew, MD

Columbia University

More Information

Publications:

Vieth R. Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards. J Nutr. 2006 Apr;136(4):1117-22.

Vieth R, Chan PC, MacFarlane GD. Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. Am J Clin Nutr. 2001 Feb;73(2):288-94.

Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999 May;69(5):842-56. Review.

Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB, Holick MF. The role of vitamin D in cancer prevention. Am J Public Health. 2006 Feb;96(2):252-61. Epub 2005 Dec 27. Review.

Bertone-Johnson ER, Chen WY, Holick MF, Hollis BW, Colditz GA, Willett WC, Hankinson SE. Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2005 Aug;14(8):1991-7.

John EM, Schwartz GG, Dreon DM, Koo J. Vitamin D and breast cancer risk: the NHANES I Epidemiologic follow-up study, 1971-1975 to 1992. National Health and Nutrition Examination Survey. Cancer Epidemiol Biomarkers Prev. 1999 May;8(5):399-406.

Shin MH, Holmes MD, Hankinson SE, Wu K, Colditz GA, Willett WC. Intake of dairy products, calcium, and vitamin d and risk of breast cancer. J Natl Cancer Inst. 2002 Sep 4;94(17):1301-11.

Lowe LC, Guy M, Mansi JL, Peckitt C, Bliss J, Wilson RG, Colston KW. Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population. Eur J Cancer. 2005 May;41(8):1164-9. Epub 2005 Apr 14.

Chen WY, Bertone-Johnson ER, Hunter DJ, Willett WC, Hankinson SE. Associations between polymorphisms in the vitamin D receptor and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2005 Oct;14(10):2335-9.

Narvaez CJ, Zinser G, Welsh J. Functions of 1alpha,25-dihydroxyvitamin D(3) in mammary gland: from normal development to breast cancer. Steroids. 2001 Mar-May;66(3-5):301-8. Review.

Mathiasen IS, Sergeev IN, Bastholm L, Elling F, Norman AW, Jäättelä M. Calcium and calpain as key mediators of apoptosis-like death induced by vitamin D compounds in breast cancer cells. J Biol Chem. 2002 Aug 23;277(34):30738-45. Epub 2002 Jun 18.

Brenner BM, Russell N, Albrecht S, Davies RJ. The effect of dietary vitamin D3 on the intracellular calcium gradient in mammalian colonic crypts. Cancer Lett. 1998 May 15;127(1-2):43-53.

Lowe L, Hansen CM, Senaratne S, Colston KW. Mechanisms implicated in the growth regulatory effects of vitamin D compounds in breast cancer cells. Recent Results Cancer Res. 2003;164:99-110. Review.

Welsh J. Vitamin D and breast cancer: insights from animal models. Am J Clin Nutr. 2004 Dec;80(6 Suppl):1721S-4S. Review.

Wolfe JN. Breast patterns as an index of risk for developing breast cancer. AJR Am J Roentgenol. 1976 Jun;126(6):1130-7.

Boyd NF, Lockwood GA, Byng JW, Tritchler DL, Yaffe MJ. Mammographic densities and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 1998 Dec;7(12):1133-44. Review.

Lee NA, Rusinek H, Weinreb J, Chandra R, Toth H, Singer C, Newstead G. Fatty and fibroglandular tissue volumes in the breasts of women 20-83 years old: comparison of X-ray mammography and computer-assisted MR imaging. AJR Am J Roentgenol. 1997 Feb;168(2):501-6.

Heywang-Köbrunner SH, Viehweg P, Heinig A, Küchler C. Contrast-enhanced MRI of the breast: accuracy, value, controversies, solutions. Eur J Radiol. 1997 Feb;24(2):94-108. Review.

Eng-Wong J, Orzano-Birgani J, Chow CK, Venzon D, Yao J, Galbo CE, Zujewski JA, Prindiville S. Effect of raloxifene on mammographic density and breast magnetic resonance imaging in premenopausal women at increased risk for breast cancer. Cancer Epidemiol Biomarkers Prev. 2008 Jul;17(7):1696-701. Epub 2008 Jun 26.

Arai M, Sasaki A, Saito N, Nakazato Y. Immunohistochemical analysis of cleaved caspase-3 detects high level of apoptosis frequently in diffuse large B-cell lymphomas of the central nervous system. Pathol Int. 2005 Mar;55(3):122-9.

Lensmeyer GL, Wiebe DA, Binkley N, Drezner MK. HPLC method for 25-hydroxyvitamin D measurement: comparison with contemporary assays. Clin Chem. 2006 Jun;52(6):1120-6. Epub 2006 Mar 30.

Gao P, Scheibel S, D'Amour P, John MR, Rao SD, Schmidt-Gayk H, Cantor TL. Development of a novel immunoradiometric assay exclusively for biologically active whole parathyroid hormone 1-84: implications for improvement of accurate assessment of parathyroid function. J Bone Miner Res. 2001 Apr;16(4):605-14.

Lee LG, Connell CR, Bloch W. Allelic discrimination by nick-translation PCR with fluorogenic probes. Nucleic Acids Res. 1993 Aug 11;21(16):3761-6.

Chlebowski, R. T., Johnson, K. C., Kooperberg, C., Hubbell, A., Lane, D., O'Sullivan, M., Cummings, S., Rohan, T., Khandekar, J., and Investigators, T. W. s. H. I. The Women's Health Initiative randomized trial of calcium plus vitamin D: effects on breast cancer and arthralgias. Proceedings of the American Society of Clinical Oncology 24, pp. LBA6. Atlanta, 2006.

Responsible Party:	Columbia University
ClinicalTrials.gov Identifier:	NCT00976339 History of Changes
Other Study ID Numbers:	AAAC3089
Study First Received:	September 11, 2009
Last Updated:	October 18, 2011
Health Authority:	United States: Food and Drug Administration

Additional relevant MeSH terms:

Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cholecalciferol
Vitamin D

Ergocalciferols
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Bone Density Conservation Agents

ClinicalTrials.gov processed this record on May 24, 2012