Retrospective analysis of the influence of 25-hydroxyvitamin D on disease progression and survival in pancreatic cancer

Vitamin D is a steroid hormone primarily obtained through the synthesis of 7-dehydrocholesterol following sun exposure, and secondarily through dietary intake of certain fish, fortified foods and beverages, and dietary supplements. The optimal serum concentration of 25-hydroxyvitamin D (25(OH)D) varies among sources. A widely accepted ideal level is 35–55 ng/mL, but other sources site a broader range of 30–70 ng/mL as optimal [1–3]. The National Health and Nutrition Examination Survey (2005 to 2006) identified a 41.6 % prevalence of vitamin D deficiency (serum 25(OH)D 20 ng/mL) in the United States [4]. Vitamin D levels are affected by ethnicity, body mass index (BMI), geographic exposure to sunlight, age, and disease [3]. Because of the vast biological role of vitamin D, especially in mechanisms commonly associated with cancer, understanding the effects of vitamin D deficiency on disease development and progression is critical.

Although the biologically active form of vitamin D is 1,25-hydroxyvitamin D (1,25(OH)₂D), total circulating vitamin D from dietary sources, supplements, and sun exposure are best represented by 25(OH)D [5, 6]. Not only is vitamin D responsible for regulating calcium and phosphorous levels in the human body, but it also has anti-proliferative and immunomodulatory effects via autocrine and paracrine signaling [1]. As a lipid-soluble molecule, it readily diffuses across plasma membranes. By binding to the vitamin D receptor (VDR) on the nucleus, it affects target genes involved in intracellular signaling pathways including cell growth, differentiation, adhesion, and apoptosis, making it of interest to study in relation to cancer [5, 6]. Alteration of such cellular mechanisms plays a critical role in cancer development and suggests a potential relationship between vitamin D and cancer.

While the relationship between serum 25(OH)D levels and cancer opens a broad area for analysis, ample research has been conducted analyzing vitamin D and risk of cancer development in prostate, breast, and colorectal cancers [3, 6–10]. Vitamin D supplements have been shown to reduce the risk of cancer development by 77 % when compared to and verified with placebos, and a 2006 study observed a 29 % reduction in cancer death rate for every 10 ng/mL increase in vitamin D [11]. Similarly, ambient exposure to ultraviolet light, especially ultraviolet B-rays (UVB), has been shown to reduce the risk of pancreatic cancer development [12–14]. Despite the evidence supporting decreased risk of pancreatic cancer in individuals with higher serum 25(OH)D, the relationship between serum 25(OH)D and its effect on pancreatic cancer progression has not been extensively studied. Pancreatic cancer is the fourth leading cause of cancer related death in the United States with a 6 % 5-year survival rate, and 75 % mortality rate within the first year of diagnosis [7, 15, 16]. Contradictory results describing the relationship between vitamin D and pancreatic cancer make it difficult for researchers to draw consistent conclusions [17, 18]. While multiple studies suggest adequate 25(OH)D levels may decrease incidence of pancreatic cancer, Stolzenberg et al. conducted a pooled, nested, case–control study of eight cohorts, finding that higher levels of vitamin D (40 ng/mL) were associated with a two-fold increase in risk of pancreatic cancer development (OR?=?2.12, 95 % CI: 1.23, 3.64) [17]. Such results suggest vitamin D supplementation in cancer patients should be monitored carefully.

Despite this data, in vitro and in vivo studies of pancreatic cancer cell lines found that 25(OH)D inhibited cell line growth, while analogs of 25(OH)D inhibited pancreatic cell proliferation, induced differentiation, promoted apoptosis in vitro, and inhibited pancreatic tumor growth in vivo [18–20]. A study published in May 2015 found that activation of vitamin D/VDR signaling led to inhibition of FOXM1, a direct transcriptional target of VDR, causing a suppression of tumor stemness, growth, and metastasis [15]. These results imply vitamin D possesses anti-tumorigenic properties that may be useful in preventing development or progression of cancer.

Although in vitro studies have identified vitamin D and its receptor as potential targets for inhibiting pancreatic cancer development or progression, genetic studies to date have not identified an association between the 25(OH)D, the VDR, and pancreatic cancer [21, 22]. In an analysis of 11 genes (213 single nucleotide polymorphisms) related to vitamin D synthesis, metabolism, and signaling, no individual genes were significantly associated with pancreatic cancer [22].

The first study (CALGB 151006) to examine the relationship between serum 25(OH)D in patients with pancreatic cancer and time to progression (TTP) and overall survival (OS) was a correlative study conducted in May 2014 [23]. These results did not support a statistically significant relationship between 25(OH)D levels and TTP or OS [23]. This current retrospective study aims to contribute to the literature exploring the relationship between vitamin D and TTP and OS in pancreatic cancer patients. It is hypothesized that lower baseline serum concentrations (BSC) of 25(OH)D will be associated with decreased TTP and OS.