Barrie R. Cassileth, MS, PhD
Integrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, of Memorial Sloan Kettering Cancer Center, New York.
Technically, vitamin D is a secosteroid hormone, not a vitamin. Increasing evidence indicates that vitamin D exerts effects beyond calcium homeostasis. Importantly, for example, higher serum vitamin D levels are associated with better cancer outcomes, including survival.1-3 The protective effects of vitamin D result from its role as a nuclear transcription factor that regulates cell growth,4 differentiation,5 and a wide range of cellular mechanisms crucial to the development and progression of cancer. Vitamin D acts as an immunomodulator through multiple pathways and enhances immune tolerance.6
Serum vitamin D levels influence both gene expression and regulation in hundreds of genes.7 Vitamin D activates the Wnt-cadherin pathway, and vitamin D deficiency permits increased colon cancer cell growth.8 Vitamin D increases aromatase inhibition9 and decreases both vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) synthesis.6
Evidence indicates that vitamin D plays a role in BRCA1-mediated cancers and may modulate triple-negative breast cancer by preventing cathepsin L–mediated degradation of 53BP1.10 BRCA1 deficiency induces increased degradation of 53BP1 in breast cancer cells, facilitating unregulated cellular growth. Because administration of vitamin D reverses the 53BP1 degradation, thus enhancing serum vitamin D levels, therapeutic benefits in triple-negative breast cancer and other BRCA1-mediated cancers may result.10
Vitamin D Synthesis
Vitamin D is predominantly synthesized in two steps: First, calcidiol (25-hydroxy vitamin D) is formed from ergocalciferol (D2) or cholecalciferol (D3) via 25-hydroxylation in the liver by CYP2R1, CYP27A1, or CYP3A4. Calcidiol then undergoes 1α-hydroxylation primarily in the kidneys via CYP27B1, resulting in its active form, calcitriol (1, 25-dihydroxy vitamin D).
Local calcitriol tissue synthesis also occurs through activation of the vitamin D receptor, driven by the serum concentration of calcidiol. Local calcitriol synthesis also has been demonstrated in cancerous cell lines in colorectal,11 breast,12 and prostate13 tissues. Because extraskeletal benefits of vitamin D are likely secondary to local synthesis, enhancing serum vitamin D levels may provide tissue-specific protective effects.
Vitamin D and Cancer Prevention
The strongest and most consistent evidence for vitamin D’s protective effects is seen in patients with colorectal14 and breast cancers.1 Some epidemiologic studies suggest that vitamin D levels of approximately 30 ng/mL may protect against breast cancer,15 whereas meta-analyses conclude at least 50 ng/mL is required to decrease the risk by 50%.16 Meta-analyses find a 50% decreased incidence of colorectal cancer with serum vitamin D levels ≥ 33 ng/mL.17
Prostate cancer data are inconsistent.18 Prostate cells can lose their vitamin D receptor as they become more anaplastic, rendering cells resistant to vitamin D’s antiproliferative effects.13 This vitamin D receptor loss provides insight into the potential mechanisms behind U-shaped survival curves, where both higher and lower serum vitamin D levels showed worse survival. Similar mechanisms may be in effect for pancreatic and other cancers, as higher levels were associated with poorer outcomes in the Vitamin D Pooling Project.19
Two prospective trials are addressing whether vitamin D3 supplementation helps prevent cancer. The VITamin D and OmegA-3 TriaL (VITAL) uses a 2×2 factorial design with vitamin D3 at 2,000 IU daily with or without omega-3 fatty acid supplementation to assess cancer and cardiovascular disease incidence in more than 20,000 subjects.20 The three-armed FINnish Vitamin D (FIND) trial administers vitamin D3 at 1,600 or 3,200 IU daily vs placebo and will study the incidence of cardiovascular disease and cancer in 18,000 participants (NCT01463813).
Different Doses May Achieve Similar Serum Levels
Vitamin D receptor genetics may contribute to the detrimental effects of low vitamin D.21 Receptor variability and medications can alter vitamin D metabolism, affecting daily vitamin D requirements needed to maintain steady serum levels. Vitamins D3 and D2 are fat-soluble; therefore, coadministration with resin binders such as cholestyramine or clinical malabsorption syndromes decrease vitamin D absorption. Vitamin D2 has a shorter half-life and is approximately 80% less potent than vitamin D3.
Calcidiol is synthesized by CYP3A4, and calcitriol induces CYP3A4. Thus, there is a theoretical potential for serum drug alterations in medications that utilize the CYP3A4 pathway. That said, a 2013 review22 concluded there was insufficient evidence regarding most interactions.
Breast Cancer and Aromatase Inhibitors
Aromatase inhibitors utilize CYP3A4, which may increase the vitamin D daily requirement. Higher serum vitamin D levels than typically achieved with most vitamin D3 maintenance doses may be required to decrease aromatase inhibitor treatment–related side effects. Vitamin D has tissue-selective aromatase inhibitor action9 and may also modulate aromatase inhibitor–associated osteoporosis.
To overcome genetic variability in receptors, monitoring vitamin D levels and titrating supplementation to achieve target levels may be more prudent than administering a single vitamin D dose to all patients. Large randomized controlled trials designed to address specific oncology-relevant endpoints are warranted to define optimal vitamin D level(s) in oncology.— Kathleen M. Wesa, MD, (top), and Barrie R. Cassileth, MS, PhD
The B-ABLE study of 232 women on aromatase inhibitors for early breast cancer showed significantly decreased aromatase inhibitor–associated bone density loss after 1 year of aromatase inhibitor treatment in women with serum vitamin D levels ≥ 40 ng/mL23 compared with levels < 30 ng/mL. Women with vitamin D ≥ 40 ng/mL at 3 months post–aromatase inhibitor initiation had reduced bone loss of 1.7% (P = .005) compared with women with levels < 30 ng/mL.
Phase II trials using vitamin D supplementation to prevent aromatase inhibitor–associated arthralgias showed increased arthralgias with vitamin D < 40 ng/mL. A pilot trial using cholecalciferol (vitamin D3) supplementation showed significantly decreased aromatase inhibitor–associated arthralgias with vitamin D levels > 66 ng/mL.24 Another randomized controlled trial using 50,000 IU of vitamin D2 showed significant reduction in arthralgias with weekly vitamin D2 administration, which dissipated once the dose was decreased to 50,000 IU monthly.25 Larger confirmatory randomized controlled trials are needed.
The Institute of Medicine (IOM),26 U.S. Preventive Services Task Force,27,28 and Endocrine Society29 published conflicting recommendations regarding vitamin D sufficiency. A 2011 IOM report recommends at least 20 ng/mL for skeletal health, whereas the Endocrine Society requires > 30 ng/mL. Neither recommendation may be applicable to the oncology setting.
Long-term vitamin D3 use of 10,000 IU daily has been shown to be safe,30 and the risk of toxicity, even with serum levels of 150 ng/mL, is minimal.31 Most intervention trials have not reported vitamin D levels > 60 ng/mL; thus, the overall risk-benefit ratio of enhanced serum levels remains undefined.
Population-based screening for vitamin D deficiency is not recommended, but determining vitamin D levels in patients at risk for falls, osteoporosis, or other complications of vitamin D deficiency is appropriate. Vitamin D testing does not ensure adequate vitamin D levels, given the inconsistency in responses to vitamin D supplementation and the wide variability in over-the-counter product potency.32
The IOM guidelines do not appear to be useful in the oncology setting. More aggressive vitamin D3 administration may be required to achieve serum vitamin D levels in a range adequate to determine the risk-benefit ratio, especially for patients receiving aromatase inhibitors.
To overcome genetic variability in receptors, monitoring vitamin D levels and titrating supplementation to achieve target levels may be more prudent than administering a single vitamin D dose to all patients. Large randomized controlled trials designed to address specific oncology-relevant endpoints are warranted to define optimal vitamin D level(s) in oncology. ■
Disclosure: Drs. Wesa and Cassileth reported no potential conflicts of interest.
18. Gilbert R, Martin RM, Beynon R, et al: Associations of circulating and dietary vitamin D with prostate cancer risk: A systematic review and dose-response meta-analysis. Cancer Causes Control 22:319-340, 2011.
19. Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, et al: Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort consortium Vitamin D Pooling Project of rarer cancers. Am J Epidemiol 172:81-93, 2010.
20. LeBoff MS, Yue AY, Copeland T, et al: VITAL-Bone Health: Rationale and design of two ancillary studies evaluating the effects of vitamin D and/or omega-3 fatty acid supplements on incident fractures and bone health outcomes in the VITamin D and OmegA-3 TriaL (VITAL). Contemp Clin Trials 41:259-268, 2015.
23. Prieto-Alhambra D, Servitja S, Javaid MK, et al: Vitamin D threshold to prevent aromatase inhibitor-related bone loss: The B-ABLE prospective cohort study. Breast Cancer Res Treat 133:1159-1167, 2012.
24. Khan QJ, Reddy PS, Kimler BF, et al: Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat 119:111-118, 2010.
25. Rastelli AL, Taylor ME, Gao F, et al: Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): A phase II, double-blind, placebo-controlled, randomized trial. Breast Cancer Res Treat 129:107-116, 2011.
26. Ross AC, Manson JE, Abrams SA, et al: The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab 96:53-58, 2011.
28. Moyer VA, U.S. Preventive Services Task Force: Prevention of falls in community-dwelling older adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 157:197-204, 2012.
29. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al: Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96:1911-1930, 2011.