A Prospective, randomized , placebo, controlled trial ( double blinded) to assess the potential role of vitamin D treatment in breast cancer patients

1. INTRODUCTION AND RATIONALE
Although the exact relationship between vitamin D and (breast) cancer remains
unclear, a growing body of evidence suggests vitamin D could account for
several favourable effects on (breast) cancer prognosis and tumour biology (1,
2).

Previously, data from epidemiological studies were inconclusive about the
effects of vitamin D and the risk of breast cancer. A recent meta-analysis of
Chen et al however, provides strong evidence for a chemopreventive effect of
vitamin D against breast cancer (3). Combining the results of 11 studies that
examined the relationship between vitamin D intake and breast cancer risk, a
significant decrease in breast cancer risk was found for those with highest
quantile of vitamin D intake compared with the lowest intake (RR=0.55, 95% CI =
0.85-0.97) (3). They also reported a significant inverse relationship between
serum 25(OH) vitamin D levels and breast cancer risk (3). However, there are no
large, prospective, randomized controlled trials administering high doses of
vitamin D to investigate effects on breast cancer risk or histology (2, 3). The
rationale is to perform such a study.

The suggestive chemopreventive effect of vitamin D is biological plausible (2).
Many tissues, including breast tissue, express 1, 25 vitamin D hydroxylase and
are thus able to convert the predominant inactive and circulating 25(OH)
vitamin D to its active 1, 25(di-OH) metabolite. This active metabolite can
bind the vitamin D receptor, present in nuclei of most cells, to form a nuclear
transcription factor regulating cell differentiation, proliferation and
apoptosis (4). This has been confirmed both in in vivo (animal experiments) and
in vitro experiments (1, 3, 5). Therefore, the rationale is to investigate
proliferation and apoptosis markers in this study.

Vitamin D is readily available, relatively safe and cheap. Breast cancer is the
most frequent malignancy in women in the Netherlands (6). Therefore, this study
could have a major impact on breast cancer management if beneficial effects of
vitamin D supplementation on breast cancer histology could be demonstrated.
There are currently no studies addressing this question in breast cancer
patients, however, we found one study currently recruiting male patients to
address this question in prostate cancer patients (7).

An published review about vitamin D administration in Multiple Sclerosis
patients confirmed the safety of vitamin D (11). In this trial patients
consuming progressively rising amounts of cholecalciferol, ending with one
month of intake at 40,000 IU/day exhibited no detectable effect on serum
calcium concentration or urinary calcium excretion. Furthermore, the published
literature contains no cases of vitamin D intoxication at long-term doses up to
40,000 IU/day (8). For these reasons, we have chosen to use 40,000 IU/day as a
maximum dose for a period up to 8 weeks.

To assess impact of high doses vitamin D on tumour histology in breast cancer
patients

prospective Randomized controlled trial

Intervention:
1. Vitamin D supplementation, 40.000 IU/day in the intervention group and
placebo in the control group, both 55 patients each. Supplementation starts
after breast cancer diagnosis is communicated with the patient and will be
continued until surgery is performed (estimated window of treatment = 3-8
weeks).
2. Blood samples will be taken at time of diagnosis and every 14 days until day
of surgery and at day of surgery

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness:
1. daily intake of Vitamin D (orally) (burden)
2. two-weekly extra blood samples and at day of diagnosis and at day of surgery
(burden)
3. the potential and biological plausible positive effects on primary tumour
and circulating tumour cells (benefit).