Vitamin D and cancer prognosis

Background

When the skin is exposed to UVB radiation, the synthesis of vitamin D (D3) begins, which is hydroxylated in the liver to calcidiol (25OHD) and further in the kidneys to the active hormone calcitriol (classical synthesis). Additionally, the synthesis of calcitriol can occur in almost all types of cells (non-classical synthesis), making calcitriol available as needed. Laboratory studies have shown that calcitriol inhibits cancer processes, but whether low and high levels of 25OHD can predict prognosis and the mechanisms that might explain such associations are uncertain. An inverse relationship between 25OHD levels and cancer mortality could have at least two explanations: (A) 25OHD inhibits cancer processes through biological mechanisms; (B) The processes and/or consequences of cancer disease lead to a decline in serum 25OHD levels (i.e., reverse causation).

Today, personalized treatment is emphasized. It is important to find biological indicators that can predict the course and outcome of the disease. Vitamin D and other associated metabolites may be potential biomarkers for identifying individuals at different risk levels for death.

Purpose

The project sheds light on:

1. Whether serum levels of vitamin D (25OHD) affect the risk of breast and colorectal cancer.
2. Whether serum levels of 25OHD at diagnosis predict prognosis.
3. Whether the association between 25OHD levels and cancer prognosis is causal.
4. Whether other metabolites related to vitamin D synthesis are associated with cancer prognosis and the potential of such metabolites as biomarkers to identify at-risk individuals.

Study design and data sources 

The project is based on data and serum samples from the Janus Serum Bank. Donors to the Janus Serum Bank (through health examinations) who later developed colorectal, breast, lung, prostate, ovarian cancer, or lymphoma and provided a diagnostic blood sample to Janus are included. Information about cancer diagnosis and death is collected from the Cancer Registry and Cause of Death Registry. Different patient groups are included in the various sub-studies, addressing different research questions.

Results 

Sub-study I: For patients with prostate cancer, we found a significant reduction in the risk of cancer death for those with moderate (77% reduction) and high (84% reduction) 25OHD levels at diagnosis, relative to those with insufficient levels. The results suggest that vitamin D may be involved in disease progression and that 25OHD levels are a possible prognostic marker for prostate cancer patients.

Sub-study II: We found similar results for patients with breast, colorectal, lung, and lymphoma cancers.

Sub-study III: In a review article, we discussed and concluded that this relationship could be causal (temporality, strength, dose-response, biological plausibility, and consistency) and that there is not a dose-response relationship, but a 25OHD level around 50 nmol/L may be a threshold level.

Sub-study IV: Using repeated serum samples from different time points relative to cancer diagnosis, we found that 25OHD levels >46 nmol/L, both long before and at diagnosis, predicted significantly better survival. Furthermore, we found that patients with 25OHD levels ≥62 nmol/L at both time points had approximately 60% lower risk of death compared to those with <46 nmol/L in both samples. Increasing 25OHD levels from the pre-diagnostic to the diagnostic sample was associated with reduced mortality. The results support a causal explanation between vitamin D and the risk of cancer death.

Sub-study V: In a case-control study, we found a linear positive relationship between serum levels of calcium and albumin and ovarian cancer. The results indicate that higher calcium levels reflect ongoing malignancy.

Sub-study VI: In a cohort study of ovarian cancer patients, we found results that support the hypothesis that calcium and albumin could be biomarkers for ongoing ovarian cancer. Monitoring changes in calcium and albumin over time could be helpful for early detection of ovarian cancer.

Sub-study VII: The Vitamin D Pooling Project (VDPP), led by the NCI, USA, is a large consortium of 17 international cohorts investigating whether vitamin D levels are related to the risk of colorectal and breast cancer to assess whether vitamin D intake can be recommended for primary prevention of these cancers.

We found no association between vitamin D levels and overall breast cancer risk, but there was a tendency towards increased risk for advanced disease and triple-negative breast cancer with low vitamin D levels (25OHD). The results also show a lower risk of colorectal cancer with higher vitamin D levels, suggesting that recommended daily vitamin D intake for primary prevention of colorectal cancer should be increased.

Project status

We intend to continue our work on investigating the relationship between longitudinal levels of 25OHD, calcium, and albumin as possible biomarkers for ongoing cancer and prognosis (uterine and ovarian).