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Breast Cancer and long term vitamin D studies – March 2013

Long follow-up time after blood draw adversely affected this nested case-control study

A letter to editor, by William B. Grant

Circulating levels of 25-hydroxyvitamin D and risk of breast cancer: a nested case-control study

Breast Cancer Research 2013, 15:R15 doi:10.1186/bcr3390

Stephanie Scarmo, Yelena Afanasyeva, Per Lenner, Karen L Koenig, Ronald L Horst, Tess V Clendenen, Alan A Arslan, Yu Chen, Göran Hallmans, Eva Lundin, Sabina Rinaldi, Paolo Toniolo, Roy E Shore and Anne Zeleniuch-Jacquotte

The paper by Scarmo and colleagues reported no correlation between serum 25-hydroxyvitamin D [25(OH)D] concentration and risk of breast cancer in the analysis of data from two cohort studies, one in New York City, the other in Sweden [1]. This result agrees with most other cohort studies but disagrees with case-control studies. The reason for the discrepancy between the two types of studies appears to be that serum 25(OH)D concentrations lose correlation with risk of breast cancer after about three years due to the rapid development of breast cancer. The evidence is as follows.

In a review, the relative risk of breast cancer was plotted vs. years of follow up after blood draw at time of enrollment. All of the case-control studies (zero years of follow up) had statistically significant inverse correlations with serum 25(OH)D concentrations as did one nested case-control study with just under three years of follow up while none of the nested case-control studies with four-to-seven years of follow up found non-significant inverse correlations with respect to serum 25(OH)D concentration at time of enrollment [2].
For colorectal cancer, which is a slowly developing cancer, significant inverse correlations were found for follow-up periods from zero to 14 years [2]. Similar findings were made for all-cause mortality rate: the regression fit to the hazard ratio vs. follow-up period changed from 0.82 at six years to 0.96 at 14 years [3]. A graph was also presented showing the change in correlation coefficient for serum 25(OH)D concentrations made at various intervals: it dropped from 0.68 at one year to 0.42 at 14 years.

There is additional evidence that breast cancer is a rapidly developing cancer: there are two seasonal peaks in breast cancer diagnosis, spring and fall [4]. The authors attributed this finding to the protective effect of vitamin D in summer and melatonin in winter.

Two graphical meta-analyses of the serum 25(OH)D-breast cancer incidence relation have been reported, one including both case-control and nested case-control studies [5], the other just case-control studies [6].

The evidence that vitamin D reduces the risk of breast cancer has been reviewed in relation to Hill’s criteria for causality [7] and found to satisfy the criteria in two reviews [8,9]. Since vitamin D can be considered a nutrient, even though it is primarily obtained from solar ultraviolet-B irradiance, Hill’s criteria are appropriate for evaluation of evidence based nutrition including vitamin D [10].

Returning briefly to Ref. 1, it is noted that for participants who donated more than two blood samples, the first and last collected prior to breast cancer diagnosis were used. Perhaps it would be worthwhile to do another analysis using only cases for which 25(OH)D concentrations less than three years prior to diagnosis of breast cancer were used. In addition, similar analyses could be done for different follow-up periods.

One other caveat is that sometimes women start taking vitamin D supplements late in life, likely due to concern about or diagnosis of osteoporosis. This idea seems to explain why elderly women have a U-shaped relation between serum 25(OH)D concentration and frailty [11] while men have an inverse correlation [12]. Thus, it would be interesting to see whether there were any marked differences in serum 25(OH)D concentration for those participants who had multiple blood draws.


1.Scarmo S, Afanasyeva Y, Lenner P, Koenig K, Horst R, Clendenen T, Arslan A, Chen Y, Hallmans G, Lundin E, Rinaldi S, Toniolo P, Shore R, Zeleniuch-Jacquotte A. Circulating levels of 25-hydroxyvitamin D and risk of breast cancer: a nested case-control study. Breast Cancer Res. 2013 Feb 26;15(1):R15. [Epub ahead of print]

2. Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level; implications for meta-analyses and setting vitamin D guidelines. Dermatoendocrinol. 2011, 3:199-204.
All-cause mortality does not relate to vitamin D tests years earlier - April 2012 in VitaminDWiki

3. Grant WB. Effect of follow-up time on the relation between prediagnostic serum 25-hydroxyitamin D and all-cause mortality rate. Dermatoendocrinol. 2012, 4:198-202.

4. Oh EY, Ansell C, Nawaz H, Yang CH, Wood PA, Hrushesky WJ. Global breast cancer seasonality. Breast Cancer Res Treat. 2010, 123:233-243.

5. Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B, 2010, 101:130-136.

6. Grant WB. A review of the evidence regarding the solar ultraviolet-B-vitamin D-cancer hypothesis. Standardy Medyczne/Pediatria. 2012, 9:610-619. in VitaminDWiki

7. Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965, 58:295-300.

8. Grant WB. How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer? An examination using Hill’s criteria for causality. Dermatoendocrinol. 2009, 1:17-24.

9. Mohr SB, Gorham ED, Alcaraz JE, Kane CI, Macera CA, Parsons JE, Wingard DL, Garland CF. Does the evidence for an inverse relationship between serum vitamin D status and breast cancer risk satisfy the Hill criteria? Dermatoendocrin. 2012, 4:152-157.

10. Biesalski HK, Aggett PJ, Anton R, Bernstein PS, Blumberg J, Heaney RP, Henry J, Nolan JM, Richardson DP, van Ommen B, Witkamp RF, Rijkers GT, Z��llner I. 26th Hohenheim Consensus Conference, September 11, 2010 Scientific substantiation of health claims: evidence-based nutrition. Nutrition. 2011, 27(10 Suppl):S1-S20.

11. Ensrud KE, Ewing SK, Fredman L, Hochberg MC, Cauley JA, Hillier TA, Cummings SR, Yaffe K, Cawthon PM; Study of Osteoporotic Fractures Research Group. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J Clin Endocrinol Metab. 2010, 95:5266-5273.

12. Ensrud KE, Blackwell TL, Cauley JA, Cummings SR, Barrett-Connor E, Dam TT, Hoffman AR, Shikany JM, Lane NE, Stefanick ML, Orwoll ES, Cawthon PM; Osteoporotic Fractures in Men Study Group. Circulating 25-hydroxyvitamin D levels and frailty in older men: the osteoporotic fractures in men study. J Am Geriatr Soc. 2011, 59:101-106.

Competing interests

I receive funding from Bio-Tech Pharmacal (Fayetteville, AR), and the Sunlight Research Forum (Veldhoven) and have received funding from the UV Foundation (McLean, VA), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada).

Reference #6 has the following chart


See also VitaminDWiki

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