Vitamin D and Cancer Risk: Is there a U-shaped association? Marji McCullough, ScD, RD Epidemiology Research Program
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1 Vitamin D and Cancer Risk: Is there a U-shaped association? Marji McCullough, ScD, RD Epidemiology Research Program American Institute for Cancer Research October 29, 204
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3 Objectives Review vitamin D recommendations Describe associations with cancer - Prostate, Colorectal, Breast Methodological challenges Vitamin D Pooling Project Future directions
4 D 3 α,25(oh) 2 D 25(OH)D Classic endocrine functions: Ca 2+ & P i absorption in intestine bone mineralization D 3, D 2 CYP-27B 25(OH)D Target Cell α,25(oh) 2 D e.g. Colon, breast, prostate CYP24A degrade Proliferation Differentiation, apoptosis Inflammation Invasion/Metastasis Angiogenesis
5 Dietary Reference Intakes (DRIs) for Vitamin D: 997 to Adults Adults UL 200 UL , , ,000 Vitamin D (IU) 40 IU= µg 600 IU=5 µg 800 IU=20 µg Institute of Medicine, National Academy of Sciences Dietary Reference Intakes for Calcium and Vitamin D (200)
6 Dietary Reference Intakes (DRIs) for Vitamin D: 997 to Adults The Adults evidence 70 for non-skeletal 997 UL effects of vitamin D was deemed insufficient to contribute to the determination of DRIs for vitamin D Vitamin D (IU) 200 UL , , ,000 Institute of Medicine, National Academy of Sciences Dietary Reference Intakes for Calcium and Vitamin D (200)
7 Vitamin D Sources 30 min. ~ 20,000 IU Dark skin 5-0X longer 3 oz ~ 800 IU Tbsp =,360 IU,000 IU 5,000 IU or Vitamin D Fortified ~00 IU
8 IOM Suggested blood 25(OH)D levels for bone health deficiency Inadequate for some sufficient no added benefit may be reason for concern (nmol/l) ng/ml 20 ng/ml 30 ng/ml Conversion factor ng/ml X = nmol/l Institute of Medicine, National Academy of Sciences Dietary Reference Intakes for Calcium and Vitamin D (200)
9 IOM and Endocrine Society suggested blood 25(OH)D levels for bone health 40% NHANES 20% deficient inadequate for some sufficient no added benefit may be reason for concern (nmol/l) deficient insufficient sufficient Endocrine Society Recommendations 250 Holick, et al J Clin Endo Metab 20
10 How does vitamin D intake (food and supplements) affect 25(OH)D levels? Amount (IU) 40 IU ( µg) Increase (nmol/l) Increase (nmol/l) 2 ~.95 ~ Wide variability in response Response greater with lower basal levels Meta-analysis of 76 RCTs (Autier, et al: J Clin Endo Metab, 202) 2 Vitamin D supplementation study (Aloia, AJCN 2008)
11 Does Vitamin D Status Alter Carcinogenesis? Hypothesis : Benefit comes from preventing deficiency Hypothesis 2: Additional benefit from optimizing serum 25OHD 3 3 Risk of Cancer 2 0 IOM Level Risk of Cancer 2 0 IOM Level Serum 25OHD (nmol/l) Serum 25OHD (nmol/l) Fleet 204
12 Is there a U-shaped curve? Hypothesis 3: Benefit from reaching a target range of serum 25OHD Risk of Cancer IOM Level Serum 25OHD (nmol/l) modified from Fleet 204
13 Prostate Cancer
14 25(OH)D and Total Prostate Cancer Risk High vs Low RR=.8 ( ) Xu, J Ca Res Clin Onc, 204
15 Is there a U-shaped curve? Hypothesis 3: Benefit from reaching a target range of serum 25OHD Risk of Cancer IOM Level Serum 25OHD (nmol/l) modified from Fleet 204
16 Baseline plasma 25(OH)D and prostate cancer risk in the SELECT RCT study population 2 All Prostate Cancer Cases (N = 73).5 RR (95% CI) <44 Q 44-<58 Q2 58-<73 Q3 73-<9 Q4 9 Q5 0 Plasma 25(OH)D (Quintiles, nmol/l) Kristal et al., Cancer Epid Biomarkers Prev 204
17 Prediagnostic 25(OH)D and Total Prostate Cancer Risk RR (95% CI) RR (95% CI) 2.5 Kristal et al., CEBP Cases/ Controls SELECT [USA] <44 Q 44-<58 Q <73 Q3 73-<9 Q4 2.5 Schenk et al., CEBP Cases/682 Controls PCPT [USA] 2 P-trend = <45 Q <57 Q2 57-<7 Q Q Q4 (nmol/>l) 2.5 Ahn et al., JNCI Cases / 78 Controls PLCO [USA] 2 P-trend = Q 43-5 Q2 5-6 Q Q4.33 No studies show protective association Q5 Most studies look like this *Associations with high grade cancer also inconsistent
18 Colorectal Cancer
19 Meta-Analysis of 25(OH)D Levels and Colorectal Cancer Risk High vs Low WHI (W) SUMMARY Summary OR: 0.66 (95% CI ) N = 2905 cases, 8 studies Odds Ratio Lee et al, Ca Prev Res 20
20 Prediagnostic 25(OH)D and Colorectal Cancer Risk 2 Weinstein et al., 204* 476 Cases/476 Controls PLCO [USA] P-trend = 0.02 RR (95% CI) Q Q2 Q3 Q4 Q5 0 *Season-specific cut-points Weinstein, et al, Int J Cancer, 204
21 Women s Health Initiative: Colorectal Cancer Risk HR=.08 (95% CI ),000 mg Ca, 400 IU Vitamin D Wactawski-Wende J et al. N Engl J Med 2006;354: N=36,282 women Wactawski-Wende J et al. N Engl J Med 2006;354:
22 Breast Cancer
23 Meta-analysis of 25(OH)D and Breast Cancer Risk High vs. Low OR=0.92 ( ) Odds Ratio Kim et al BJC 204
24 Prediagnostic 25(OH)D and Breast Cancer Risk 2 Bertone-Johnson et al., CEBP, 2005* 70 Cases/724 Controls NHS [USA] P-trend = Freedman et al., CEBP, Cases/005 Controls PLCO [USA] P-trend = RR (95% CI) Q Q2 Q3 Q4 Q5 0.5 Q <46 Q2 46-<59 Q3 59-<7 Q4 7-<84 Q (nmol/) *Quintile cut-points are batch-specific.
25 Women s Health Initiative: Breast Cancer (,000 mg Calcium/400 IU vitamin D) HR: 0.96 (95% CI ) N=36,282 women Chlebowski, JNCI, 2007
26 Challenges in Comparing Studies Inter-assay and laboratory differences Accounting for seasonal variation Different adjustment for confounders
27 Vitamin D Pooling Project of Breast and Colorectal Cancer ( VDPP ) CARET WHI MEC CPS II PLCO NYUWHS CLUE II HPFS NHS NHS II PHS WHS BGS MALMO NSHDS JANUS E3N ORDET ATBC EPIC (0 European countries) White: both sites (n=3) Pink: breast cancer Yellow: colorectal cancer JPHC n = 2 studies 7 breast cancer studies; n=,696 cases 7 colorectal cancer studies; n=6,032 cases
28 VDPP - Methods Calibrate previously measured 25(OH)D to common lab (Heartland Assays, Ames IA) Uniform season standardization Uniform control for confounders using original data
29 VDPP preliminary results slides removed
30 Future Directions
31 VITAL RCT THE VITAMIN D AND OMEGA-3 TRIAL (VITAL) RCT in 20,000 U.S. men and women 2000 IU Vitamin D or gram omega-3 fatty acids, or both vs placebo Outcomes: all cancer, prostate, breast and colorectal cancer, heart disease and stroke Dose determined based on desired target range nmol/l Participants allowed to take recommended amounts of vitamin D Manson, et al, Contemp Clin Trials 202
32 Conclusions Calibrated, standardized, pooled analyses help elucidate shape of vitamin D-cancer association What is the shape of the association for these cancers from the published literature? Breast: Inconsistent Colorectal: Mostly inverse Prostate: Unclear; possible U-shape Limited available data at levels > 00 nmol/l
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