# Presentation: 442787

## Vitamin D and Cancer

***Lee Helman, M.D.***
***Scientific Director for Clinical Research***
***June 17, 2008***

## Outline

**Background**
- Metabolism, catabolism, and VDR polymorphisms
**Recent Conflicting Studies**
**NCI Funded Studies**
**Future Studies/Needs**

## Vitamin D in the news 

- Vitamin D in the news

- No Dodging Prostate Cancer With Vitamin D

**Vitamin D May Help Curb Breast Cancer, Study Finds**

**Vitamin D Deficiency Worsens Breast Cancer?**

- Study backs Vitamin D in cancer fight

**‘****Sunshine vitamin’ may ward off breast cancer**

**Notes:**
Vitamin D studies have repeatedly been in the news the last few months and years

## Recent NIH Conferences

- 2003
- Vitamin D and Health in the 21st Century: Bone and Beyond
- May 2007
- Vitamin D and Cancer: Current Dilemmas/Future Needs
- Sept 2007
- Vitamin D and Health in the 21st Century: An Update

- Deeb et al (2007) Nature Reviews Cancer 7, 684-700

**24-Ohase (CYP24A1)**

**1********-OHase**

**25-OHase**

**Notes:**
---Vitamin D is a fat-soluble vitamin that is naturally present in very few foods, added to others, and available as a dietary supplement. It is also produced endogenously when ultraviolet rays from sunlight strike the skin and trigger vitamin D synthesis 
--Vitamin D obtained from sun exposure, food, and supplements is biologically inert and must undergo two hydroxylations in the body for activation. The first occurs in the liver and converts vitamin D to 25-hydroxyvitamin D [25(OH)D], also known as calcidiol. The second occurs primarily in the kidney and forms the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D], also known as calcitriol].
--Vitamin D is essential for promoting calcium absorption in the gut and maintaining adequate serum calcium and phosphate concentrations to enable normal mineralization of bone and prevent hypocalcemic tetany. It is also needed for bone growth and bone remodeling by osteoblasts and osteoclasts 
--Without sufficient vitamin D, bones can become thin, brittle, or misshapen. 
--Vitamin D sufficiency prevents rickets in children and osteomalacia in adults. Together with calcium, vitamin D also helps protect older adults from osteoporosis.
--Vitamin D has other roles in human health, including modulation of neuromuscular and immune function and reduction of inflammation. 
--Many genes encoding proteins that regulate cell proliferation, differentiation, and apoptosis are modulated in part by vitamin D
--Many laboratory-cultured human cells have vitamin D receptors and some convert 25(OH)D to 1,25(OH)2D. It remains to be determined whether cells with vitamin D receptors in the intact human carry out this conversion.
--Serum concentration of 25(OH)D is the best indicator of vitamin D status. It reflects vitamin D produced cutaneously and that obtained from food and supplements and has a fairly long circulating half-life of 15 days. 
--However, serum 25(OH)D levels do not indicate the amount of vitamin D stored in other body tissues. Circulating 1,25(OH)2D is generally not a good indicator of vitamin D status because it has a short half-life of 15 hours and serum concentrations are closely regulated by parathyroid hormone, calcium, and phosphate
--Levels of 1,25(OH)2D do not typically decrease until vitamin D deficiency is severe.
---There is considerable discussion of the serum concentrations of 25(OH)D associated with deficiency (e.g., rickets), adequacy for bone health, and optimal overall health. A concentration of <20 nanograms per milliliter (ng/mL) (or <50 nanomoles per liter [nmol/L]) is generally considered inadequate.
infants, children=200-400 IU 14-50=200 IU 
50-70= 400 IU
70+=600 IU

African American’s typically have vit D deficiency

## Vitamin D Implications in Cancer

- Breast

- Prostate/Ovarian

- Colon

- Pancreas

- Lung

**Notes:**
Laboratory and animal evidence as well as epidemiologic data suggest that vitamin D status could affect cancer risk. 

Strong biological and mechanistic bases indicate that vitamin D plays a role in the prevention of colon, prostate, and breast cancers. 

Emerging epidemiologic data suggest that vitamin D has a protective effect against colon cancer, but the data are not as strong for a protective effect against prostate and breast cancer, and are variable for cancers at other sites. 

Studies do not consistently show a protective effect or no effect, however. One study of Finnish smokers, for example, found that subjects in the highest quintile of baseline vitamin D status have a three-fold higher risk of developing pancreatic cancer.
(Source NIH Office of Dietary Supplements)

Garland et al review (AJPH, 96(2):252, 2006) states pubmed search (done in 2004) found 63 observational studies on vit D and cancer risk, 30 colon, 13 breast, 26 prostate, 7 ovarian
Most found protective relationship b/w vit D and lower risk of cancer

## Conflicting Evidence

- Vitamin D emerged as a protective factor in a prospective, cross-sectional study of 3,121 adults aged ≥50 years (96% men) who underwent a colonoscopy.
- The study found that 10% had at least one advanced cancerous lesion. Those with the highest vitamin D intakes (>645 IU/day) had a significantly lower risk of these lesions.
- Daily supplementation of calcium (1000 mg) with vitamin D (400 IU) for seven years had no effect on the incidence of colorectal cancer among postmenopausal women in the Women’s Health Initiative *Wactawski-Wende et al (2006) NEJM, 354:7*
- More recently, a clinical trial focused on bone health in 1,179 postmenopausal women residing in rural Nebraska found that subjects supplemented daily with calcium (1,400-1,500 mg) and vitamin D3 (1,100 IU) had a significantly lower incidence of cancer over 4 years compared to women taking a placebo.

**Notes:**
However, the Women's Health Initiative, in which 36,282 postmenopausal women of various races and ethnicities were randomly assigned to receive 400 IU vitamin D plus 1,000 mg calcium daily or a placebo, found no significant differences between the groups in the incidence of colorectal cancers over 7 years.  But serum VitD2 levels only went from 42 to 47 nmol/L 

Source:
Office of Dietary Supplements

## Vitamin D and Cancer Incidence

**Lappe, J. M et al. Am J Clin Nutr 2007;85:1586-1591**

**Kaplan-Meier survival curves (ie, free of cancer) for 3 treatment groups randomly assigned in the entire cohort of 1179 women**

**Notes:**
Higher dose of 1100Iu D3 daily.  Baseline D2 levels 72nmol/liter in all groups, same at 12 months except in the D3 suplemented group, it rose to 96nmol/L
Even if first year deaths are discounted (already exist) still found significant differences
Problem-Cancer not a primary outcome variable in this study!

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**Dietary Vitamin D and Colorectal Cancer**

- Gorham E., et al.  J Steroid Biochem Mol Biol. 97:179-94, 2005

- Odds ratio

## DCEG Vitamin D studies

- Examine the prospective relationship between the vitamin D status metabolite, 25-hydroxyvitamin D in serum and cancer mortality
- The study was conducted in more than 16,000 persons aged 17 and older who participated in the Third National Health and Nutrition Examination survey (NHANES III)
- Found total cancer mortality was unrelated to baseline vitamin D status in the entire population, men, women, non-Hispanic whites, non-Hispanic blacks, Mexican Americans in persons younger than 70 or 70 years or older
- Found no interaction between vitamin D and season or vitamin D and serum retinol
- Colorectal cancer mortality was inversely related to serum 25(OH)D level
- levels >80 nmol/L were associated with a 72% risk reduction than those <50 nmol/L** **

- Freeman et al, JNCI, (2007) 99(21):1594

**Notes:**
A total of 536  cancer deaths in 146578 person years

## Clinical Trials

**571 trials on Vitamin D **
**217 trials on Vitamin D and cancer **
**77 trials on Vitamin D and cancer sponsored by NIH**

## NCI-sponsored trials

- Phase III Randomized Study of Zoledronate, Vitamin D, and Calcium With or Without Strontium Chloride Sr 89 or Samarium Sm 153 Lexidronam Pentasodium in Preventing or Delaying Skeletal-Related Events in Patients With Bone Metastases Secondary to Prostate, Lung, or Breast Cancer-Radiation Therapy Oncology Group--NCI
- Phase II Pilot Study of Vitamin D Deficiency and Myalgias and/or Arthralgias in Postmenopausal Women Receiving Adjuvant Letrozole for Stage I-III Breast Cancer-Fred Hutchinson Cancer Research Center
- Vitamin D and Soy Supplements in Treating Patients With Recurrent Prostate Cancer--Wake Forest University
- DNA Changes That Affect Vitamin D Metabolism in Patients With Colorectal Cancer Receiving Vitamin D Supplements--Roswell Park Cancer Institute
- Vitamin D in Treating Patients With Prostate Cancer-- Roswell Park Cancer Institute
- Vitamin D/Calcium Polyp Prevention Study--Dartmouth-Hitchcock Medical Center

**Notes:**
77 on clinical trials.gov with vit d and cancer funded by NIH

## NCI funding 

- Search CRSIP FY08 funding of vitamin D by NCI
- 67 grants funded
- 41 R01s
- 9 R03s
- Remaining 17 are: K07, K01, R41, F3, R21, P01, U54, P50, U10, K07, U01, P30

## DCEG- Ongoing Vitamin D Studies

- Examining the relationship between two vitamin D metabolites (25(OH)D and 1,25(OH)D) and breast cancer in Prostate, Lung, Colon, and Ovarian screening study cohort
- Recently published no association found between vitamin D concentration in blood and risk of prostate cancer (Ahn et al, JNCI (2008) 100(11):796-804)
- We are also examining the relationship between pre-diagnostic 25(OH)D and lymphoid cancer risk in a case-control study nested in the Alpha-Tocopherol Beta Carotene Prevention Study cohort of Finnish smokers.
- Investigators in REB are also participating in a large pooled analysis of the association between 25(OH)D and several cancers, including pancreatic, upper GI, renal, endometrial, and ovarian cancer and NHL.
- The USRT project is also planning a study to assess the determinants of circulating vitamin D by examining self-reported host skin characteristics, sun exposure, and supplement and dietary behavior.
- Currently undertaking a small study to examine the methodological issues in blood samples measurement of 25(OH)D

**Notes:**
REB radiation epidemiology branch
USRT-US radiologic technologists study sponsored by Univ Minn and NCI

## VDR genotype, Vit D levels and Cancer risk

- Li et al, PLoS Med. (2007) 4(3):562-71

**Notes:**
FokI polymorphisms at the translation initiation codon
T/C polymorphism-C variant “F” allele lacks first ATG, initiates from second ATG resulting in shorter VDR-greater trascriptional activity
T variant “f” allele initiates at first ATG.  In caucasian series of prostate cancer allele distribution FF 41%, Ff 38%, and ff 21%
But a previous study from Standord found ff associated with less aggressive histotype in 191 patients with prostate Ca (Ca Epi, Biomarkers and Prevention 2003)

Gene nutrient interactions

Low level of vit D and an ff genotype in vit D receptor your risk of prostate cancer is 2.5

## Cancer Mortality by Annual Sun Exposure

**Colon Cancer**

**Breast Cancer**

**Garland, C. F. et al. Am J Public Health 2006;96:252-261**

- Copyright ©2006 American Public Health Association

**Notes:**
Cancer mortality rates are higher in areas with less sunlight

Age-adjusted colon cancer mortality rates, by county area, and contours of annual mean daily solar irradiance in Langleys (calories/cm2), United States, 1970–1994

Age-adjusted breast cancer mortality rates, by county area, and contours of annual mean daily solar irradiance in Langleys (calories/cm2), United States, 1970–1994

## HHS Report asks..

- Evidence Report/Technology Assessment, Number 158
- Effectiveness and Safety of Vitamin D in Relation to Bone Health
- AHRQ Publication No. 07-E013, August 2007
- Prepared for: Agency for Healthcare Research and Quality
- U.S. Department of Health and Human Services
- By: University of Ottawa Evidence-based Practice Center

-  “...did not retrieve any systematic reviews in our literature search that addressed this question
-  This highlights an area for future research
-  Suggested sun exposure times for vitamin D synthesis will vary with individual and environmental characteristics such as latitude and skin pigmentation (melanin)”

**Is There a Level of Sunlight Exposure That Is Sufficient to Maintain Adequate Vitamin D Concentrations, But Does Not Increase the Risk of Skin Cancer?**

**Notes:**
Our search strategy may not have identified studies in the dermatology or cancer literature that evaluated the effect of UV exposure in terms of minimal erythemal dose (MED) on risk of skin cancer. An ecological study in Australia by Samanek et al. used daily ultraviolet index data to derive sun exposure times (1/6 – 1/3 MED) for fair-skinned people based on current reference vitamin D intakes. Solar exposure times for 15 percent of the body surface at noon in summer were short and varied from 2-10 minutes depending on the latitude. The authors stated that it is impractical to provide a uniform message to the general population given the number of individual and environmental variables that need to be taken into consideration (e.g., latitude, time of day, skin pigmentation).261 A recently published study used a vitamin D action spectrum and U.S. reference conditions to calculate UV exposure times comparable to 1,000 IU
vitamin D.

- Deeb et al (2007) Nature Reviews Cancer 7, 684-700

**24-Ohase (CYP24A1)**

**1********-OHase**

**25-OHase**

**Notes:**
---Vitamin D is a fat-soluble vitamin that is naturally present in very few foods, added to others, and available as a dietary supplement. It is also produced endogenously when ultraviolet rays from sunlight strike the skin and trigger vitamin D synthesis 
--Vitamin D obtained from sun exposure, food, and supplements is biologically inert and must undergo two hydroxylations in the body for activation. The first occurs in the liver and converts vitamin D to 25-hydroxyvitamin D [25(OH)D], also known as calcidiol. The second occurs primarily in the kidney and forms the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D], also known as calcitriol].
--Vitamin D is essential for promoting calcium absorption in the gut and maintaining adequate serum calcium and phosphate concentrations to enable normal mineralization of bone and prevent hypocalcemic tetany. It is also needed for bone growth and bone remodeling by osteoblasts and osteoclasts 
--Without sufficient vitamin D, bones can become thin, brittle, or misshapen. 
--Vitamin D sufficiency prevents rickets in children and osteomalacia in adults. Together with calcium, vitamin D also helps protect older adults from osteoporosis.
--Vitamin D has other roles in human health, including modulation of neuromuscular and immune function and reduction of inflammation. 
--Many genes encoding proteins that regulate cell proliferation, differentiation, and apoptosis are modulated in part by vitamin D
--Many laboratory-cultured human cells have vitamin D receptors and some convert 25(OH)D to 1,25(OH)2D. It remains to be determined whether cells with vitamin D receptors in the intact human carry out this conversion.
--Serum concentration of 25(OH)D is the best indicator of vitamin D status. It reflects vitamin D produced cutaneously and that obtained from food and supplements and has a fairly long circulating half-life of 15 days. 
--However, serum 25(OH)D levels do not indicate the amount of vitamin D stored in other body tissues. Circulating 1,25(OH)2D is generally not a good indicator of vitamin D status because it has a short half-life of 15 hours and serum concentrations are closely regulated by parathyroid hormone, calcium, and phosphate
--Levels of 1,25(OH)2D do not typically decrease until vitamin D deficiency is severe.
---There is considerable discussion of the serum concentrations of 25(OH)D associated with deficiency (e.g., rickets), adequacy for bone health, and optimal overall health. A concentration of <20 nanograms per milliliter (ng/mL) (or <50 nanomoles per liter [nmol/L]) is generally considered inadequate.
infants, children=200-400 IU 14-50=200 IU 
50-70= 400 IU
70+=600 IU

African American’s typically have vit D deficiency

## Vitamin D Anticancer Properties

- Alterations in vitamin D receptor expression, and in the synthesis (25-hydroxylase and 1α-hydroxylase) and catabolism (24-hydroxylase) of vitamin D metabolites are involved in the growth regulation of tumors; thus, compromising 1α,25(OH)2D3 (also known as calcitriol; the active metabolite of vitamin D signalling) sensitivity and 1α,25(OH)2D3 signalling
- The antiproliferative effects of 1α,25(OH)2D3 have been demonstrated in various tumour types, as determined by preclinical trials
- The anti-tumor effects of 1α,25(OH)2D3 involve mechanisms that are associated with G0/G1 arrest, differentiation, induction of apoptosis and modulating different signalling pathways in tumor cells, as well as inhibiting tumor angiogenesis
- Glucocorticoids potentiate the anti-tumor effects of 1α,25(OH)2D3 and decrease 1α,25(OH)2D3
- 	-induced hypercalcemia. 1α,25(OH)2D3 also potentiates the antitumor effects of many chemotherapeutic agents such as platinum analogues, taxanes and DNA-intercalating agents
- Given that the major vitamin D catabolizing enzyme, CYP24A1 (24-hydroxylase), is often amplified and overexpressed in tumor cells, agents that inhibit this enzyme can potentiate 1α,25(OH)2D3 anti-tumor effects
- Preclinical data indicate that maximal anti-tumor effects are seen with pharmacological doses of 1α,25(OH)2D3, and can be safely achieved in animals using a high-dose, intermittent schedule of administration. Some clinical trial data indicates that 1α,25(OH)2D3 is well-tolerated in cancer patients within a proper dosing schedule
- Data support the hypothesis that vitamin D compounds may have an important role in cancer therapy and prevention, and merit further investigation

- Deeb et al, (2007) Nature

## Future Direction/needs 

- Further research is needed to:
- Determine whether vitamin D inadequacy increases cancer risk
- Whether greater exposure to the nutrient is protective
- Need to consider metabolism, catabolism, and VDR polymorphisms
- Address methodology to measure serum vitamin D level --biomarkers
- Need surrogate markers of Vit D activity
- Determine molecular targets for vitamin D
- Explore vitamin D/sun exposure dilemma