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Archived Comments for: Plasma 25-hydroxyvitamin D3 is associated with decreased risk of postmenopausal breast cancer in whites: a nested case–control study in the multiethnic cohort study

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  1. Comments on serum 25-hydroxyvitamin D level and breast cancer risk

    William B. Grant, SUNARC

    27 May 2014

    The paper by Kim et al. [1] found that serum 25-hydroxyvitamin D [25(OHD)] levels were inversely correlated with breast cancer incidence rates for postmenopausal white women living in Los Angeles and Hawaii but not for women of other ethnic groups. The authors noted that circulating 25(OH)D has not generally been found correlated with breast cancer incidence.

    Overlooked in their paper was any discussion of how the follow-up period affects the findings. The longer the follow-up period, the less likely it is to find an inverse correlation between serum 25(OH)D level and breast cancer incidence [2] and all-cause mortality rate [3] due to changes in serum 25(OH)D level with respect to time. The effect for breast cancer is particularly strong since breast tumors grow very fast. For example, breast cancer diagnoses are more frequent in spring and fall, with vitamin D reducing risk in summer and melatonin reducing risk in winter [4]. Only observational studies with follow-up periods less than about three years have found significant inverse correlations between serum 25(OH)D level and breast cancer incidence [2]. The study by Kim et al. [1] had a follow-up period of 3.1 years.

    Case-control studies with serum 25(OH)D level measured near time of breast cancer diagnosis have very consistently found pronounced inverse correlations between serum 25(OH)D level and incidence rates of breast cancer [5]. A graphical meta-analysis of the case-control study results with a power law fit to the data found the adjusted odds ratio starting at 1.0 at 8.0 ng/ml, dropping to 0.56 at 20 ng/ml, 0.39 at 30 ng/ml, and 0.22 at 40 ng/ml [5]. While there is concern about the possibility of "reverse causality", i.e., that the disease state could affect serum 25(OH)D levels, there is no evidence to support this possibility for vitamin D and breast cancer. Those who develop breast cancer are unaware that they have breast cancer until it is diagnosed, so would not modify oral vitamin D intake or sun exposure habits. There is also no evidence that cancer reduces serum 25(OH)D levels through physiological processes. The high consistency of case-control studies of breast cancer incidence rates with respect to serum 25(OH)D levels for studies from Germany, Mexico, the UK, and the US indicates that it is a robust relation.

    Regarding the non-white ethnic groups, there may be unmodeled factors that are more important than serum 25(OH)D levels for these groups. For example, a multicountry ecological study found that the three most important risk factors for breast cancer were energy supply from animal products, gross domestic product, and smoking [6]. Alcohol consumption is also an important breast cancer risk factor [7]. None of these factors was considered by Kim et al. If those from different ethnic groups had much higher or lower values for such risk factors, it could have affected the findings. However, solar ultraviolet-B doses have been found inversely correlated with breast cancer mortality rates in ecological studies of African-Americans [8]

    1.Kim Y, Franke AA, Shvetsov YB, Wilkens LR, Cooney RV, Lurie G, Maskarinec G, Hernandez BY, Le Marchand L, Henderson BE, et al. Plasma 25-hydroxyvitamin D3 is associated with decreased risk of postmenopausal breast cancer in whites, a nested case-control study in the multiethnic cohort study. BMC Cancer. 2014 Jan 17,14(1),29. [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(3),199-204.
    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(2),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(1),233-43.
    5. Grant WB. A review of the evidence regarding the solar ultraviolet-B–vitamin D–cancer hypothesis. Standardy Medyczne/Pediatria. 2012,9,610-9.
    6. Grant WB. A multicountry ecological study of cancer incidence rates in 2008 with respect to various risk-modifying factors, Nutrients. 2014,6(1),163-189.
    7. Coronado GD, Beasley J, Livaudais J. Alcohol consumption and the risk of breast cancer. Salud Publica Mex. 2011,53(5),440-7.
    8. Grant WB. Lower vitamin-D production from solar ultraviolet-B irradiance may explain some differences in cancer survival rates. J Natl Med Assoc. 2006,98(3),357-64

    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).