Vitamin D and circulating tumor cells in primary breast cancer
Front Oncol. 2022 Sep 7;12:950451. doi: 10.3389/fonc.2022.950451
Michal Mego 1 2 , Barbora Vlkova 3 , Gabriel Minarik 3 , Zuzana Cierna 4 5 , Marian Karaba 6 , Juraj Benca 6 7 , Tatiana Sedlackova 3 , Dana Cholujova 8 , Paulina Gronesova 8 , Katarina Kalavska 2 , Daniel Pindak 6 9 , Jozef Mardiak 1 , Peter Celec 3
Background: Circulating tumor cells (CTCs) contribute to the metastatic cascade and represent an independent survival predictor in breast cancer (BC) patients. Vitamin D has pleiotropic effects, and its low concentrations are associated with breast cancer and metastasis. The aim of this study was to assess plasma vitamin D in primary BC patients in relation to CTCs.
Methods: This study included 91 non-metastatic BC patients (stage I-III) and 24 healthy donors. Blood samples for the analyses were drawn at the time of surgery. CTCs were assessed using a quantitative RT-PCR assay for expression of epithelial (CK19) or epithelial-to-mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, and ZEB1). Total 25-OH vitamin D was measured in plasma using ELISA. Plasma cytokines and angiogenic factors were measured by enzyme-linked immunoassay.
Results: CTCs were detected in 30 (33%) patients.
Patients with detectable CTCs in peripheral blood had significantly lower vitamin D concentrations in comparison to patients without detectable CTCs (mean ± SD)
- 8.50 ± 3.89 µg/L for CTC-positive vs
- 9.69 ± 3.49 µg/L for CTC-negative patients, p = 0.03).
The mean ( ± SD) vitamin D plasma level was
- 9.3 ± 3.65 µg/L for breast cancer patients compared to
- 18.6 ± 6.8 for healthy donors (p < 0.000001).
There was no association between plasma vitamin D and other patient/tumor characteristics. Plasma vitamin D levels are inversely correlated with plasma TGF-β1, TGF-β2, IL β, IL-5, and eotaxin (all p < 0.05).
Patients with vitamin D above the median had a better overall survival (hazard ratio (HR) = 0.36, 95% CI 0.16-0.80, p = 0.017), and combined analysis showed the best survival for CTC-negative patients with vitamin D levels above the median as compared to patients with opposite characteristics (HR = 0.18, 95% CI 0.05-0.63, p = 0.004).
Conclusions: Low vitamin D could be a consequence and hence a biomarker of a more invasive disease. Alternatively, vitamin D could be associated with survival because of its role in tumor dissemination. Whether its supplementation affects the metastatic cascade should be tested in animal experiments and interventional studies.
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