Safety, Feasibility and Efficacy of Vitamin D Supplementation in Women With Metastatic Breast Cancer (SAFE-D)

Study Aims

Several clinical trials are underway to investigate if vitamin D2 or D3 provided at various doses (10,000-50,000 IUs/week) can improve the side-effects associated with anti-estrogen therapies, specifically aromatase inhibitors (AIs). However, these current trials use variable forms of vitamin D and predominantly include women with Stage I-III disease, excluding women with metastatic breast cancer. Evaluation of the safety of vitamin D3 supplementation is crucial since supplementation can lead to hypercalcemia and importantly, in vitro studies have shown that vitamin D3 influences the transcription of a gene that increases estrogen production.27,28 To assure that vitamin D3 does not abrogate the clinical effects of anti-estrogen therapies, the effect of vitamin D3 supplementation on estrogen production requires evaluation. Therefore, the overarching goal of this pilot study is to evaluate the safety, feasibility and efficacy of vitamin D3 supplementation in women with MBC. We will address and test the following aims and hypotheses, respectively:

Aim 1: To determine if weekly supplementation of 50,000 IUs of vitamin D3 raises serum levels of 25(OH)D to >30 mg/dl without adverse effects.

Hypothesis 1: Women who are compliant with vitamin D3 supplementation, as evidenced by normalization (>30 mg/dl) or increases in their serum 25(OH)D levels, will not experience significant changes in serum calcium, parathyroid hormone or serum estradiol levels.

Aim 2: To determine the effect of vitamin D3 supplementation on symptom management.

Hypothesis 2: Women who achieve serum concentrations of 25 (OH)D ≥30 mg/dl or experience significant increases in 25(OH)D will exhibit improvements in pain, fatigue, sleep, mood, muscle function and overall quality of life.

Exploratory Aim: To explore the mechanistic effects of vitamin D3 supplementation on inflammatory markers and its potential association with symptom management.

Summary: Evidence from studies involving early stage breast cancer participants confirms that musculoskeletal pain, endocrine related symptoms and mood disturbances are commonly associated with breast cancer treatment, particularly hormone deprivation therapies. The high prevalence of vitamin D deficiency/insufficiency among breast cancer survivors is well accepted and further hypothesized to aggravate treatment-related side effects, particularly arthralgias. Women with MBC are excluded from the majority of on-going vitamin D supplementation trials for safety and generalizability purposes. However, novel therapies are continuing to improve and prolong the lives of these women, resulting in a rapidly expansive group of breast cancer survivors. While vitamin D supplementation is prescribed to correct an underlying nutrient deficiency in the clinical context of preserving bone health, emerging evidence suggests it may have more systemic effects. Thus, vitamin D repletion/supplementation has profound potential implications for women with MBC, whose primary goal of treatment is to minimize the side-effects of treatment in support of optimal quality of life. This study reflects a highly innovative, yet simple therapy that could ultimately provide these survivors with a much needed evidence-based supportive care strategies.

Inclusion criteria

• Metastatic breast cancer (Stage IV)
• Histologically confirmed estrogen receptor positive disease
• Female
• Serum 25(OH) <30 ng/ml
• Age ≥ 18 years
• Pre or post-menopausal
• ECOG Performance status 0-2
• Adequate organ function as defined as GFR> 30 mls/min and serum calcium ≤ 10.4 mg/dl
• Any race/ethnicity
• English speaking
• No changes to MBC treatments within 30 days of enrollment and/or deemed clinically stable by their treating physician
• Willingness to sign a written informed consent and complete questionnaires
• Cease ingestion of vitamin D supplementation not study related

Exclusion criteria

• Women with Stage I-III breast cancer
• Serum 25(OH)D levels ≥ 30 ng/ml
• Untreated CNS involvement
• History of kidney stones
• History of renal failure
• History of hyperparathyroidism
• History of hypersensitivity to vitamin D
• Non-English speaking
• Currently pregnant or lactating, or anticipating pregnancy
• Unwilling to cease ingestion of calcium supplements (>1000 mg/d)
• Unwilling or unable to complete informed consent or study questionnaires
• Psychiatric or other clinical conditions that preclude study compliance
• Other important medical or safety considerations at the discretion of the investigator and/or study physician, including non-compliance with the study therapy or other activities