Negative Impact of Vitamin D Deficiency at Diagnosis on Breast Cancer Survival: A Prospective Cohort Study

Objective. We prospectively evaluated the association between vitamin D concentration at diagnosis and overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) in postmenopausal women treated for breast cancer. Methods. This study included 192 patients newly diagnosed with invasive breast cancer, aged ≥45 years, and serum 25-hydroxy vitamin D (25 (OH)D) concentration assessment at diagnosis. Patients were classified into groups according to 25 (OH)D concentrations: sufficient (≥30 ng/mL), insufficient (between 20 and 29 ng/mL), and deficient (<20 ng/mL). The primary outcome was OS, and the secondary outcomes were DFS and CSS. The Kaplan–Meier curve and Cox regression model were used to assess the association between 25 (OH)D concentrations and survival rates. Differences in survival were evaluated by hazard ratios (HRs). Results. The mean age was 61.3 ± 9.6 years, 25 (OH)D concentration was 26.9 ± 7.5 ng/mL (range 12.0–59.2 ng/mL), and the follow-up period was between 54 and 78 months. Sufficient 25 (OH)D was detected in 33.9% of patients, insufficient in 47.9%, and deficient in 18.2%. A total of 51 patients (26.6%) died during the study period, with a mean OS time of 54.4 ± 20.2 months (range 9–78 months). Patients with 25 (OH)D deficiency and insufficiency at diagnosis had a significantly lower OS, DFS, and CSS compared with patients with sufficient values (). After adjustment for clinical and tumoral prognostic factors, patients with 25 (OH)D concentrations considered deficient at diagnosis had a significantly higher risk of global death (HR, 4.65; 95% CI, 1.65–13.12), higher risk of disease recurrence (HR, 6.87; 95% CI, 2.35–21.18), and higher risk of death from the disease (HR, 5.91; 95% CI, 1.98–17.60) than the group with sufficient 25(OH)D concentrations. Conclusion. In postmenopausal women treated for breast cancer, vitamin D deficiency and insufficiency at diagnosis were independently associated with lower OS, DFS, and CSS compared with patients with sufficient 25(OH)D concentrations.

1. Introduction
Breast cancer is the type of cancer that mostly affects women in the world, in both developing and developed countries, with about 2.3 million new cases in 2020, comprising 25% of all cancers diagnosed in women [1]. In Brazil, the National Cancer Institute (INCA) estimates 66,280 new cases of breast cancer, for each year of the 2020–2022 triennium [2]. According to data from the American Cancer Society, the 5- and 10-year relative survival rates for women with invasive breast cancer are 90% and 84%, respectively [1]. Despite being considered a relatively good prognosis cancer if diagnosed and treated in a timely manner, the AMAZONA study demonstrated that Brazilian women have a higher risk of being diagnosed with late-stage breast cancer and at a younger age than women in high-income countries [3].

Vitamin D concentration can be considered a prognostic factor in women with breast cancer [4, 5]. Vitamin D is a steroid hormone that has various physiologic effects on several tissues [6]. The major source of vitamin D is endogenous synthesis in the skin (dermis and epidermis). When the skin is exposed to sunlight, 7-dehydrocholesterol absorbs UVB radiation, leading to chemical bonds within the 7-dehydrocholesterol molecule to break and rearrange, resulting in the formation of previtamin D3. In the skin, previtamin D3 undergoes rapid thermally induced transformation to vitamin D3. Cutaneously synthesized vitamin D3 is released from the plasma membrane and is transported to the liver, where it is hydroxylated at carbon 25 to 25-hydroxy vitamin D (25 (OH)D). The activation of vitamin D requires hydroxylation of 25 (OH)D at position 1 in the proximal renal tubules. This step is catalyzed by the enzyme 1α-hydroxylase, which converts 25 (OH)D to 1,25-dihydroxyvitamin D (1,25(OH)2D), the biologically active form of vitamin D [7, 8].

The main organs where vitamin D acts are those involved in calcium homeostasis, including bones, intestine, and kidneys, but most tissues of the body express vitamin D receptor (VDR), including the mammary gland [6]. These receptors were also present in a breast cancer cell line, suggesting a possible association between vitamin D and cancer [9]. The effects of the active form of vitamin D (1,25(OH)2D) on the breast are mediated by VDR, which controls the expression of genes that regulate antineoplastic actions, such as cell proliferation, differentiation, and apoptosis, which is in accordance with scientific evidence linking hypovitaminosis D to breast cancer incidence and mortality [10, 11]. The antiproliferative effect of 1,25(OH)2D cancer cells has since been confirmed in most normal and cancerous cells whereby 1,25(OH)2D especially inhibits cell cycle progression at the G1 stage. The VDR was not a marker for malignancy but might play a role in the pathogenesis or evolution of cancer [9]. Demonstrating the role of vitamin D in cancer mortality, an updated meta-analysis of randomized controlled trials (RCTs) found that vitamin D supplementation was associated with 13% reduced cancer mortality over 3–10 years of follow-up [12].