Vitamin D and Cancer Risk: Is there a U-shaped association? · • 2000 IU Vitamin D or 1 gram omega-3 fatty acids, or both vs placebo • Outcomes: all cancer, prostate, breast and

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, 2014

Objectives

• Review vitamin D recommendations • Describe associations with cancer - Prostate, Colorectal, Breast • Methodological challenges • Vitamin D Pooling Project • Future directions

25(OH)D

Classic endocrine functions: ↑ Ca2+ & Pi absorption in

intestine ↑ bone mineralization

↓ Proliferation ↑ Differentiation, apoptosis

↓ Inflammation ↓ Invasion/Metastasis

↓ Angiogenesis

1α,25(OH)2D

CYP-27B1

D3, D2

D3

Target Cell

CYP24A1

25(OH)D

1α,25(OH)2D

e.g. Colon, breast, prostate

degrade

Dietary Reference Intakes (DRIs) for Vitamin D: 1997 to 2010

Institute of Medicine, National Academy of Sciences Dietary Reference Intakes for Calcium and Vitamin D (2010)

400 600 800 1,000 . . . 2,000 . . . 4,000

Vitamin D (IU)

Adults

≥70

2010

1997 UL Adults

1997

2010 UL

40 IU= 1 µg 600 IU=15 µg 800 IU=20 µg

Dietary Reference Intakes (DRIs) for Vitamin D: 1997 to 2010


400 600 800 1,000 . . . 2,000 . . . 4,000

Vitamin D (IU)

Adults

≥70

2010

1997 UL Adults

1997

2010 UL “The evidence for non-skeletal effects of vitamin D was deemed insufficient to

contribute to the determination of DRIs for vitamin D”

Vitamin D Sources

3 oz ~ 800 IU

or

~100 IU

1 Tbsp = 1,360 IU

30 min. ~ 20,000 IU Dark skin 5-10X longer

Vitamin D Fortified 1,000 IU – 5,000 IU

0 25 50 75 100 125 150

(nmol/L)

deficiency

IOM Suggested blood 25(OH)D levels for bone health

12 ng/ml 30 ng/ml

Inadequate for some sufficient

no added benefit

may be reason for concern


20 ng/ml Conversion factor ng/mL X 2.496 = nmol/L

0 25 50 75 100 125 150

(nmol/L)

deficient

IOM and Endocrine Society suggested blood 25(OH)D levels for bone health

inadequate for some sufficient

no added benefit

may be reason for concern

250 Endocrine Society Recommendations

Holick, et al J Clin Endo Metab 2011

deficient insufficient sufficient

40% NHANES 20%

How does vitamin D intake (food and supplements) affect 25(OH)D levels?

Amount (IU)

Increase (nmol/L)1

Increase (nmol/L)2

40 IU (1 µg)

~1.95 ~0.66

600 29 10

Response greater with lower basal levels

1Meta-analysis of 76 RCTs (Autier, et al: J Clin Endo Metab, 2012) 2Vitamin D supplementation study (Aloia, AJCN 2008)

Wide variability in response

Hypothesis 1: Benefit comes from preventing deficiency

Hypothesis 2: Additional benefit from optimizing serum 25OHD

Fleet 2014

Does Vitamin D Status Alter Carcinogenesis?

0 20 40 60 80 100

3

2

1

0

Risk

of C

ance

r

Serum 25OHD (nmol/L)

0 20 40 60 80 100

3

2

1

0

Risk

of C

ance

r


IOM Level

IOM Level

Hypothesis 3: Benefit from reaching a target range of serum 25OHD

modified from Fleet 2014

Is there a “U-shaped curve”?

0 20 40 60 80 100

3

2

1

0

Risk

of C

ance

r


IOM Level

Prostate Cancer

25(OH)D and Total Prostate Cancer Risk

RR=1.18 (1.07-1.30)

Xu, J Ca Res Clin Onc, 2014

High vs Low

Hypothesis 3: Benefit from reaching a target range of serum 25OHD

modified from Fleet 2014

Is there a “U-shaped curve”?

0 20 40 60 80 100

3

2

1

0

Risk

of C

ance

r


IOM Level

Baseline plasma 25(OH)D and prostate cancer risk in the SELECT RCT study population

1

0.83 0.74

0.86 0.98

<44 Q1

44-<58 Q2

58-<73 Q3

73-<91 Q4

≥91 Q5

0

0.5

1

1.5

2

RR (9

5% C

I)

Plasma 25(OH)D (Quintiles, nmol/L)

All Prostate Cancer Cases (N = 1731)

Kristal et al., Cancer Epid Biomarkers Prev 2014

Prediagnostic 25(OH)D and Total Prostate Cancer Risk

No studies show protective association

Most studies look like this

RR (9

5% C

I)

1

0.83 0.74 0.86 0.98

<44 Q1

44-<58 Q2

58-<73 Q3

73-<91 Q4

≥91 Q5

0.5

1

1.5

2

2.5 Kristal et al., CEBP 2014 1731 Cases/ Controls

SELECT [USA]

1 1.1

1.53

1.33 1.18

13-43 Q1

43-51 Q2

51-61 Q3

61-72 Q4

72-130 Q5 0.5

1

1.5

2

2.5 Ahn et al., JNCI 2008 749 Cases / 781 Controls

PLCO [USA] P-trend = 0.20

1

0.97 1.07 1.1

<45 Q1

45-<57 Q2

57-<71 Q3

≥71 Q4 0.5

1

1.5

2

2.5 Schenk et al., CEBP 2014 1695 Cases/1682 Controls

PCPT [USA] P-trend = 0.20

RR (9

5% C

I)

(nmol/>L)

*Associations with high grade cancer also inconsistent

Colorectal Cancer

Meta-Analysis of 25(OH)D Levels and Colorectal Cancer Risk

Lee et al, Ca Prev Res 2011 N = 2905 cases, 8 studies

Summary OR: 0.66 (95% CI 0.54–0.81)

Odds Ratio

WHI (W)

SUMMARY

High vs Low

Prediagnostic 25(OH)D and Colorectal Cancer Risk

1 1.05

0.89 0.8

0.59

Q1 Q2 Q3 Q4 Q5

0

1

2 Weinstein et al., 2014* 476 Cases/476 Controls


*Season-specific cut-points

RR (9

5% C

I)

Weinstein, et al, Int J Cancer, 2014

Wactawski-Wende J et al. N Engl J Med 2006;354:684-696

Wactawski-Wende J et al. N Engl J Med 2006;354:684-696

Women’s Health Initiative: Colorectal Cancer Risk

HR=1.08 (95% CI 0.86-1.34)

1,000 mg Ca, 400 IU Vitamin D

N=36,282 women

Breast Cancer

Meta-analysis of 25(OH)D and Breast Cancer Risk

Kim et al BJC 2014 Odds Ratio

OR=0.92 (0.83-1.02)

High vs. Low

Prediagnostic 25(OH)D and Breast Cancer Risk

1

0.95

0.74 0.77 0.73

Q1 Q2 Q3 Q4 Q5

0

0.5

1

1.5

2 Bertone-Johnson et al., CEBP, 2005* 701 Cases/724 Controls

NHS [USA] P-trend = 0.06

1 1.02

1.36

1.13 1.04

Q1 <46

Q2 46-<59

Q3 59-<71

Q4 71-<84

Q5 ≥84

0

0.5

1

1.5

2 Freedman et al., CEBP, 2005 1005 Cases/1005 Controls


*Quintile cut-points are batch-specific.

RR (9

5% C

I)

(nmol/)

Women’s Health Initiative: Breast Cancer

Chlebowski , JNCI, 2007

(1,000 mg Calcium/400 IU vitamin D)

N=36,282 women

HR: 0.96 (95% CI 0.85-1.09)

Challenges in Comparing Studies

• Inter-assay and laboratory differences • Accounting for seasonal variation • Different adjustment for confounders

EPIC (10 European countries)

ATBC

JPHC

MEC

ORDET CPS II

PLCO

CLUE II

NYUWHS

HPFS NHS NHS II PHS WHS

CARET WHI

Vitamin D Pooling Project of Breast and Colorectal Cancer (“VDPP”)

n = 21 studies 17 breast cancer studies; n=11,696 cases 17 colorectal cancer studies; n=6,032 cases

JANUS

MALMONSHDS

E3N

BGS

White: both sites (n=13) Pink: breast cancer Yellow: colorectal cancer

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

VDPP preliminary results – slides removed

Future Directions

THE VITAMIN D AND OMEGA-3 TRIAL (VITAL)

• RCT in 20,000 U.S. men and women • 2000 IU Vitamin D or 1 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 75-90 nmol/L • Participants allowed to take recommended

amounts of vitamin D

http://www.vitalstudy.org/ Manson, et al, Contemp Clin Trials 2012

VITAL RCT

• 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 > 100 nmol/L

Conclusions

Vitamin D and Cancer Risk: Is there a U-shaped association? · • 2000 IU Vitamin D or 1 gram omega-3 fatty acids, or both vs placebo • Outcomes: all cancer, prostate, breast and

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