No Breast Cancer association with Vitamin D (none had enough) – Jan 2023

Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts

Eur J Epidemiol . 2023 Jan;38(1):11-29. doi: 10.1007/s10654-022-00921-1
Publisher wants $50 for the PDF PDF can be viewed on free DeepDyve trial

After callibration there were no Vitamin D levels > 30 ng

Yet figure 2 shows many studies with > 30 ng

Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42-68) years at blood collection and 63 (49-75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64).
Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50- < 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations (< 20 nmol/L, 3% of controls) or high concentrations (100- < 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95-1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection.
Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.

17 Trials

1. Beta-Carotene and Retinol Efficacy Trial (CARET)
2. CLUE II: Campaign Against Cancer and Heart Disease (CLUE II)
3. Cancer Prevention Study-II (CPS-II)
4. Multiethnic Cohort Study (MEC)
5. Nurses’ Health Study (NHS)
6. Nurses’ Health Study II (NHSII)
7. New York University Women’s Health Study (NYU WHS)
8. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)
9. Women’s Health Initiative (WHI)
10. Women’s Health Study (WHS)
11. Breakthrough Generations Study (BGS)
12. Etude Epidémiologique auprès de femmes de l'Education Nationale (E3N)
13. European Investigation into Cancer and Nutrition (EPIC)
14. JANUS Serum Bank (JANUS)
15. Malmd Diet and Cancer Study
16. Northern Sweden Health and Disease Study (NSHDS)
17. Hormones and Diet in the Etiology of Breast Cancer (ORDET)

Vitamin D Life – Overview Breast Cancer and Vitamin D contains

• 24 Meta-analyses of Vitamin D and Breast Cancer
    example: 2X reduction of deaths from Breast Cancer if have enough Vitamin D.
• Appears that having lots of Vitamin D will reduce by 3 X the chance of Breast Cancer
     wonder just how much more proof is needed
• Breast Cancer 4X more likely if have poor genes
•     Cancer - Breast category listing has 252 items along with related searches
• Breast Cancer treatment – Vitamin D was the most-popular supplement – Jan 2023
• Breast Cancer again associated with low vitamin D – 15th meta-analysis Sept 2020
• Vitamin D reduced Breast Cancer mortality in 9 out of 9 studies, yet still no consensus – April 2019
• Vitamin D both prevents and treats Breast Cancer – 2019

Previous Charts of Breast Cancer and Vitamin D ( >40 ng is good)

• Breast Cancer Mortality reduced 60 percent if more than 60 ng of Vitamin D – meta-analysis June 2017
• 
• Modeling Cancer RCTs – including Breast Cancer – April 2017 Dr. Grant
• 
• Breast Cancer 80 percent less likely if high level of vitamin D – June 2018
• 

A poor Vitamin D Receptor may result in higher BC risk than poor Vitamin D

• Vitamin D Receptor has
• Has the risk of Breast Cancer due to poor Vitamin D Receptor increased in past decades?
• 

This list is automatically updated

(Rejected) Letter to Editor by Dr. Grant

The recent article by Visvanathan et al. conducted a pooled analysis of 17 prospective cohort studies of breast cancer incidence with respect to baseline serum 25-hydroxyvitamin D [25(OH)D] concentration in an effort to determine whether vitamin D reduces risk of breast cancer [1]. Even though the range of 25(OH)D concentration extended from <20 nmol/L to >125 nmol/L, no significant correlations between 25(OH)D concentration and incidence of breast cancer were found. As the authors noted in the introduction, there is compelling evidence that vitamin D can inhibit cancer initiation and progression in experimental models. Thus, two questions arise: 1 – has vitamin D status been found to reduce risk of breast cancer incidence using other epidemiological approaches?; and, 2 – what might be the problem with prospective observational studies for breast and other types of cancer?
Regarding the first question, both case-control (CC) studies with serum 25(OH)D concentrations measured near time of breast cancer diagnosis and geographical ecological studies have found strong support for vitamin D and solar UVB dose, an index of vitamin D production, in reducing breast cancer incidence and/or mortality rates [2]. CC studies are usually overlooked regarding the role of vitamin D in health outcomes for two reasons: 1 – that the disease state might affect serum 25(OH)D concentrations (reverse causality); and 2 – that the choice of controls might introduce bias. As for the disease state affecting 25(OH)D concentrations, as was discussed in 2, it is mainly found with acute inflammatory illnesses that reduce serum 25(OH)D concentrations near the time of disease onset.
A good example is COVID-19, for which the body’s immune response often includes rapidly raising proinflammatory cytokine concentrations, thereby raising inflammatory biomarkers such as C-reactive protein, and reducing 25(OH)D concentrations. The physiological indication is a fever. However, the increase in C-reactive
protein associated with cancer incidence is very small, and cancer patients do not have fevers. As for matching
controls, approaches such as propensity score matching are now being applied, which helps ensure that cases and
controls are well matched. Also, since the findings for breast cancer risk reduction with respect to 25(OH)D
concentrations from CC studies are very similar, it does not appear that bias is an important concern.
What are the problems with prospective observational studies of cancer with respect to serum 25(OH)D
concentrations? As shown in 2011, the longer the follow-up time, the smaller the observed difference in cancer
incidence rates between high and low baseline 25(OH)D concentrations 3. In Figure 1 of [3], for four studies with
>4 years of follow up, no significant reductions of breast cancer with respect to 25(OH)D concentration were found.
(This is essentially the same as for the 17 studies included in [1] as in that article’s Figure 3.) However, for CC
studies and one prospective study with a 3-year follow up, the mean relative risk (RR) for breast cancer incidence
with respect to 25(OH)D concentrations was near 0.6 and was significant for all studies. For colorectal cancer
(CRC), RR was significantly below one out to 14 years of follow up. As mentioned in [3], there is evidence that
breast cancer tumors can develop very rapidly to a size that is easily detected. That is consistent with the fact that
breast cancer screening is recommended every one-to-two years, while CRC screening is recommended every ten
years.
It is noted that a meta-analysis of 17 cohort studies regarding CRC incidence from this consortium found a
significantly reduced odds ratio (OR) for CRC incidence with respect to serum 25(OH)D concentration for women,
but not for men 4. As shown in Figure 1 in [2] for a similar analysis of OR vs. follow-up time for CRC showed
that when the OR are plotted vs. median follow-up time to diagnosis, the OR for zero years of follow up is 0.77 for
males and 0.74 for females, in stark contrast to their finding that results were not significant for men. The reason
why no significant reduction in CRC risk was found for men is that the slope of the OR for men was 0.031/year
while that for women was 0.0081/year. Why the slopes differ is not known.

Additional support for the fact that breast cancer tumors can grow rapidly to detectable size is given in an analysis of breast cancer seasonality [5]. They included observational studies from 64 global regions over time spans from 2 to 53 years. The primary finding was that in the northern hemisphere, breast cancer incidence is more frequently detected from September through November and again from February or March through May or June, with the
minimum of detection in July and August and a weaker minimum from December to February until April. They
hypothesized that solar UVB production of vitamin D explained the summer minimum, and that increased melatonin
due to weak solar radiation levels in winter explained the winter minimum. They cited a number of articles
regarding the role of melatonin in reducing risk of breast cancer. Figure 5 in [5] shows a model pattern for relative
breast tumor volume vs. time oscillating from lower in summer and winter, higher in spring and fall, superimposed
on a continuously rising trend.

Conclusion: The role of vitamin D in reducing risk of breast and other cancers should be evaluated using findings
from mechanism studies, geographical ecological studies, observational studies using either short follow-up times
after blood draw for serum 25(OH)D concentration measurements or correction for long follow-up times, and
properly designed randomized controlled trials, i.e., based on serum 25(OH)D concentrations, enrolling participants
with low 25(OH)D concentrations, and giving large vitamin D doses [2]. In addition, the assumptions regarding the
reliability of various approaches should be carefully studied.

Funding: The author declares that no funds, grants, or other support were received during the preparation of this manuscript.
Competing Interests: I receive funding from Bio-Tech Pharmacal, Inc. (Fayetteville, AR, USA).
References

• 1. Visvanathan K, Mondul AM, Zeleniuch-Jacquotte A, et al. Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts. Eur J Epidemiol. 2023. doi:10.1007/s10654-022-00921-1
• 2. Muñoz A, Grant WB. Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms. Nutrients. 2022;14(7):1448. doi:10.3390/nu14071448
• 3. 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. doi:10.4161/derm.3.3.15364
• 4. McCullough ML, Zoltick ES, Weinstein SJ, et al. Circulating Vitamin D and Colorectal Cancer Risk: An International Pooling Project of 17 Cohorts. J Natl Cancer Inst. 2019;111(2):158-69. doi:10.1093/jnci/djy087
• 5. 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. doi:10.1007/s10549-009-0676-7

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