Breast cancer: women with sufficient levels of vitamin D have 27% lower odds of dying

Breast cancer patients who have adequate levels of vitamin D – the “sunshine vitamin” – at the time of their diagnosis have better long-term outcomes, a new study finds.

Combined with the results of prior research, the new findings suggest “an ongoing benefit for patients who maintain sufficient levels [of vitamin D] through and beyond breast cancer treatment,” said study lead author Song Yao. He’s a professor of oncology in the department of cancer prevention and control at Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.

The study also found that Black women had the lowest vitamin D levels, which might help explain their generally poorer outcomes after a breast cancer diagnosis, Yao’s group said.

The findings were presented at the recent virtual annual meeting of the American Society of Clinical Oncology.

One oncologist unconnected to the research said the findings could offer women a simple new way to fight breast cancer.

Vitamin D “can be found in some foods and is made when sunlight strikes human skin,” explained Dr. Alice Police, a breast cancer researcher at Northwell Health’s Katz Institute for Women’s Health, in Westchester, N.Y.

“This may be an opportunity for an important intervention in breast cancer outcomes for all women, but particularly in the Black population,” she said.

The study involved nearly 4,000 patients who had their vitamin D levels checked and were followed for a median of almost 10 years.

The patients were divided into three levels: vitamin D deficient (less than 20 nanograms per milliliter in blood tests); insufficient (20 to 29 ng/ml); or sufficient (30 or more ng/ml).

The study wasn’t designed to prove cause and effect. However, it found that—compared to women deficient in the nutrient—women with sufficient levels of vitamin D had 27% lower odds of dying of any cause during the 10 years of follow-up, and 22% lower odds for death from breast cancer specifically.

The team also found that the association between vitamin D levels and breast cancer outcomes was similar regardless of the tumor’s estrogen receptor (ER) status. The association appeared somewhat stronger among lower-weight patients and those diagnosed with more advanced breast cancers.

“Our findings from this large, observational cohort of breast cancer survivors with long follow-up provide the strongest evidence to date for maintaining sufficient vitamin D levels in breast cancer patients, particularly among Black women and patients with more advanced-stage disease,” Yao said in a Roswell Park news release.

Dr. Paul Baron is chief of breast surgery and director of the Breast Cancer Program at Lenox Hill Hospital in New York City. He wasn’t involved in the new research, but called it “an important study, as it shows the significance of sufficient vitamin D levels towards improving long-term survival for breast cancer patients.”

For her part, Police said the findings highlight the importance for women of adequate vitamin D.

The difference in outcomes between Black and white breast cancer patients “narrowed with higher vitamin D levels at the time of diagnosis,” she noted. “This could be an important step in efforts to level the playing field for this disease: Let the sunshine in!”

Because these findings were presented at a medical meeting, they should be considered preliminary until published in a peer-reviewed journal.

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The vitamin D hormone controls the activity of thousands of protein-encoding human genes [1]. Therefore, optimum levels are likely to be important for health. Synthesis of vitamin D in human skin depends on solar UVB radiation, whose levels are low at high latitudes, as in the United States and Europe, and highest at equatorial latitudes [2]. High concentration of melanin, the brown-black pigment in skin, is appropriate for the high UV radiation dose regions such as in the tropical plains as it absorbs UVB radiation absorption, thereby reducing production of free radicals and destruction of folate, but permitting adequate vitamin D production [3]. At higher latitudes, where the UVB radiation dose is lower [2], the rate of synthesis of vitamin D correspondingly decreases, potentially disrupting many metabolic functions that depend on that vitamin and leading to poorer health.

Here we discuss various aspects of such latitude–skin color mismatch and health disparities. By latitude–skin color mismatch, we mean that skin pigmentation is not appropriate for the solar UV doses at various latitudes, either too dark as for African Americans (defined as people living in the United States with some African ancestry) to efficiently produce vitamin D, or too light to protect against the harmful effects of UV radiation as for people living close to the equator, such as those with Anglo-Celtic ancestry in Australia. (Note that people of African descent have dark melanin, called eumelanin, while Anglo-Celtics have yellow-to-reddish melanin called pheomelanin.) This mismatch is particularly impactful in African Americans, whose dark skin is well adapted to the high UVB levels at low equatorial latitudes [3]. However, as a legacy of slavery and more recent migration, African Americans now reside at higher latitudes than in their ancestral environments. That geographic shift is largely responsible for a high prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) levels < 20 ng/mL) in African Americans [4,5] independent of diet and other factors [6]. This high prevalence of deficiency potentially contributes to many health disparities. Because vitamin D deficiency can be easily remedied by supplementation or, to a lesser extent, fortification of food, the health implications of this deficiency are important to understand.

Many factors adversely affect the health of African Americans, including high rates of poverty [7], poor housing and residential environments [8], and lack of access to affordable health care. Living in racially segregated, poor neighborhoods also exposes residents to risk of crime [9], thereby limiting time spent outdoors, as well as reducing access to well-stocked grocery stores and pharmacies. Limited educational opportunities frequently result in having jobs with high social interaction and thus greater risk of COVID-19. The high incarceration rate of African American males has resulted in many children being raised by single mothers. While these factors play important roles in racial health disparities and require sustained efforts to correct at individual and societal levels, vitamin D deficiency can be corrected rapidly and inexpensively. In this review we examine the potential health benefits of addressing this deficiency.

This narrative review considers the potential health effects of inadequate vitamin D in humans. Although the motivation for this review is the high prevalence of vitamin D deficiency in African Americans, we draw on the literature from all populations because our underlying biology is similar across all racial groups, even though the prevalence of exposures, here serum levels of 25(OH)D, can differ greatly. Thus, the findings have implications for other groups with darker skin and low 25(OH)D levels, such as US immigrants from Mexico and South Asia, and for European Americans with limited sun exposure. (The term European Americans is used to represent white, non-Hispanic Americans.)

When they are available, we cite meta-analyses or pooled primary data from multiple studies. Because ideal randomized trials are often difficult or impossible to conduct, conclusions regarding causality will usually need to be based on the weight of evidence from multiple types of study [10]. The strengths and limitations of the various approaches to determine relationships between vitamin D and health outcomes are presented in the Appendix A. Ideally, vitamin D’s health effects in populations with dark skin would be evaluated directly in such groups, but in most studies the number of such participants has been too small to evaluate separately. Nevertheless, we highlight studies of subgroups of African Americans and Hispanics (17% of the U.S. population) when available. We also pay special attention to subgroups with low baseline serum levels of vitamin D in randomized trials as this where an effect of supplementation may be expected to be seen; failure to do this may lead to misleading negative conclusions. In some randomized trials comparing vitamin D supplements with a placebo, those with low serum levels of 25(OH)D are excluded for ethical reasons and/or are treated, again potentially leading to misleading conclusions.

Current Status of Knowledge
Vitamin D: Synthesis and Metabolism

Vitamin D3 is synthesized in human skin by the UVB-dependent conversion of 7-dehydrocholesterol to vitamin D3 (herein referred to as vitamin D when used as a supplement). Vitamin D3 is then converted to 25(OH)D3, a precursor of the crucial vitamin D steroid hormone, 1,25-dihydroxyvitamin D3, or calcitriol, in a reaction requiring magnesium [11,12], which is widely deficient in the American diet [13]. Calcitriol binds to a specific binding protein, the vitamin D receptor (VDR). The resulting complex interacts with human DNA regulatory sequences known as vitamin D response elements (VDREs; 15 bases long), which reportedly vary in number between a few thousand to ten thousand [14,15]. VDREs respond specifically to calcitriol by activating or inactivating their adjacent genes [16,17,18]; this response may vary depending on the location of the VDRE and level of 25(OH)D [15]. The unusually large number of calcitriol-responsive DNA sites strongly suggests that sufficiently high 25(OH)D levels, which may vary by outcome are necessary for optimal health and longevity [16,19].

Evolution of Skin Pigmentation

Skin pigmentation is an evolutionary response to the intense solar UVB at low latitudes, where early humans evolved. Dark skin, through the presence of abundant melanin, protected humans living in Africa, southern India, and other parts of Asia against strong UVB, which causes severe sunburn, damages DNA, and destroys skin folate [3,20,21,22].

According to a widely accepted hypothesis, people in ancient times moved from low to higher latitudes, and skin pigment evolved (by several mutations) to be lighter, depending on distance from the equator, permitting more efficient production of vitamin D [3,23,24,25,26].

Others have suggested that lighter skin resulted from the acquisition of genetic variants from populations that immigrated into northern Europe, but this is still compatible with production of vitamin D being the initial selective factor for these variants [27].

(These authors also hypothesize that variations in genes encoding for proteins responsible for the transport, metabolism and signaling of vitamin D provide alternative mechanisms of adaptation to a life in northern latitudes without suffering the consequences of vitamin D deficiency. However, such mechanisms and loss of melanin are not mutually exclusive, and in either case they would leave people of African descent now living in northern latitudes at risk of vitamin D deficiency.)

The importance of solar exposure is illustrated by findings that Africans with dark skin living at low latitudes have levels of 25(OH)D of 29 to 46 ng/mL [28,29,30], that are substantially higher than those of African Americans (mean 25(OH)D ~16 ng/mL) [31]. These differences, and the similarity in levels of 25(OH)D in European Americans and Africans living in Africa, are shown in Figure 1 [32].

Thus, darker skin pigmentation in Africans living in Africa appears to allow adequate vitamin D synthesis while protecting against sunburn and other damage. Direct genetic evidence that melanin reduces synthesis of vitamin D is provided by findings that Nigerians with albinism have significantly higher 25(OH)D levels than those with normal pigmentation [33].

The interaction between skin melanin and sunlight was further illustrated in a study of pregnant women in the southeastern US; the ratios of winter-to-summer prevalence of vitamin D insufficiency were 3.58 (95% CI 1.64 to 7.81) for European-American, 1.52 (95% CI 1.18 to 1.95) for Hispanic, and 1.14 (95% CI 0.99 to 1.30) for African-American women [34].

In contrast to the slow migration in ancient times, in more recent times there was rapid movement of equatorial Africans to various regions, such as North America, due to slave transport. When the destination is at higher northern latitudes than that of the ancestral country of origin, a mismatch between skin color and UV radiation occurs and lower UVB penetration of the skin to the layer with 7-dehydrocholesterol results in deficient endogenous vitamin D production. The consequent health problems can take years to manifest and thus are both subtle and insidious. A reverse mismatch occurs when light-skinned individuals move to low latitudes (e.g., an Irish person moving to Australia), resulting in increased risk for severe sunburn (and later, high rates of skin cancer). The reverse mismatch is recognized quickly and can be mitigated by using hats and sunscreen.

Vitamin D and Health Outcomes
Most epidemiologic studies of vitamin D and health outcomes have used plasma or serum levels of 25(OH)D to measure vitamin D status. That approach has the advantage of integrating intake, solar exposure, skin color, and genetic factors. A single measure of 25(OH)D serves as a good measure of long-term status for an individual; however, the within-person correlation between 25(OH)D levels decreases as follow-up time increases [42]. Downstream metabolites of 25(OH)D are too variable over time to serve as a stable indicator of vitamin D status [43]. Other indicators of vitamin D status, such as parathyroid hormone, may improve our assessment [44], but have not yet been widely used in epidemiologic studies. Some studies have used vitamin D intake calculated from food intake, with or without supplements.

Skeletal Health

Adequate vitamin D has long been recognized as essential for bone health, and the 2011 Institute of Medicine (IOM) review of vitamin D requirements concluded that rickets and osteomalacia were the only established consequences of low vitamin D status [36].

Thus, the relation to osteomalacia served to set recommendations for vitamin D intake: the estimated average requirement (EAR—at which half the population is deficient and half is not) for serum 25(OH)D was set at 16 ng/mL. On this basis also, levels below 12 ng/mL were considered deficient, 12 to 20 ng/mL were considered “at risk of inadequacy”, and levels above 20 ng/mL were considered sufficient for 97% of the population.

Other groups have defined deficiency as levels below 30 ng/mL [45]. Since 2011, much additional evidence has supported the important effects of vitamin D beyond bone health, and the relation between serum levels of 25(OH)D and these health outcomes cannot be assumed to be the same as that with osteomalacia.

Serum levels of 25(OH)D are positively associated with bone mineral density in both European Americans and African Americans [46], but Africans and African Americans have long been known to have higher bone mineral density (BMD) [47] and lower risk of fragility fractures than Europeans [48]. Possible mechanisms may be that African Americans have higher calcium retention, lower calcium excretion, and greater bone resistance to parathyroid hormone than European Americans [47,49,50].

The reason why populations migrating from Africa to higher latitudes evolved to have weaker bones is unclear, but in the context of low UV radiation a trade-off for reductions in pelvic deformity and obstructed labor has been suggested [51]. Whatever the mechanisms, the greater bone strength of African Americans, and the assumption that the only consequence of low 25(OH)D levels is poor bone health, seems to have led many to believe that the low serum levels 25(OH)D in African Americans are not a concern. Notably, the 2011 IOM review of vitamin D did not emphasize the high prevalence of vitamin D deficiency in African Americans, even by their strictest definition of less than 12 ng/mL, and concluded that “requirements are being met by most if not all persons in both countries [US and Canada]”.

A finding of low levels of vitamin D-binding protein (VDBP) in African Americans, and thus presumably higher biologically active vitamin D, has been suggested as an explanation for healthy bone mass in African Americans despite low 25(OH(D level [52]. However, the report of low VDBP levels was subsequently shown to be an artifact of the monoclonal antibody assay used in that study; when measured by a polyclonal method or proteomic assay, levels of VDBP were similar in African- and European Americans [53]. This, and findings of much higher 25(OH)D levels in Africans living traditional lifestyles in equatorial regions, support the conclusion that the low levels of African Americans are not “natural” but due to environmental factors, primarily inadequate sun exposure.

Cancer

For many cancers, African Americans have higher incidence and mortality rates than European Americans; disparities exist for cancers of the bladder, breast, colon, endometrium, lung, ovary, pancreas, prostate, rectum, testes, and vagina, and for Hodgkin’s lymphoma [73,74] (Table 2).

Higher incidence and lower survival both contribute to some of those differences; for 2008–2012, African American males had a 12% higher overall cancer incidence and a 27% higher mortality rate than white men, whereas African American females had a 4% lower incidence rate but a 14% higher mortality rate than white women [74]. In many of the analyses, these differences in cancer rates were adjusted for a variety of potential confounding variables. Smoking, a major cause of cancer, does not account for the disparities because smoking rates for African Americans and European Americans are similar [74].

Table 2

Incidence and mortality rates for select cancers in the U.S. for males and females, 2008–2012 [74].

Sex and Cancer Type	Incidence *	Mortality **
Black	White	Black/White Ratio	Black	White	Black/White Ratio
Male
Prostate	208.7	123.0	1.70	47.2	19.9	2.38
Lung	93.4	79.3	1.18	74.9	62.2	1.20
Colorectal	60.3	47.4	1.27	27.6	18.2	1.52
Kidney	24.2	21.8	1.11	5.7	5.9	0.97
Liver	16.5	9.3	1.77	12.8	7.6	1.69
Stomach	15.1	7.8	1.93	9.4	3.6	2.58
Female
Breast	124.3	128.1	0.97	31.0	21.9	1.42
Lung	51.4	58.7	0.87	36.7	41.4	0.89
Colorectal	44.1	36.2	1.22	18.2	12.9	1.41
Kidney	13.0	11.3	1.15	2.6	2.3	1.13
Stomach	8.0	4.3	2.30	4.5	1.8	2.48
Liver	4.8	3.2	1.52	4.4	3.1	1.43

* Age-adjusted cases/100,000/yr; ** Age-adjusted deaths/100,000/yr.

In single-country geographical ecological studies, solar UVB doses are inversely associated with mortality rates for many cancers among white people [75], and within the U.S. similar inverse associations are seen among both European Americans and African Americans [76,77,78].

Variables related to socioeconomic status can be hard to account for completely, especially in ecological studies. However, among male health professionals with similar education and occupation, African Americans with few risk factors for hypovitaminosis D had risks of cancer similar to those of white men; in contrast, African-American men with several risk factors for hypovitaminosis D had a 57% higher total cancer incidence and 127% higher cancer mortality rate [79].

Risk factors for hypovitaminosis D in this population included living in a region with low solar UVB doses, not spending much recreational time out of doors, and not taking vitamin D supplements. The excess risks were greater for digestive-tract cancers. The mechanisms by which vitamin D may reduce risk of cancer incidence and death include effects on cellular differentiation, proliferation, and apoptosis; anti-angiogenesis; and anti-metastasis [80], as well as anti-inflammatory [80,81] and immune-enhancing [82] mechanisms.

Colorectal cancer. Among various malignancies, low vitamin D status has been most consistently associated with colorectal cancer. In ecological analyses within the United States, colorectal cancer (CRC) mortality among European Americans has been lowest in southwestern states and highest in northeastern states, and lowest in the southern states and highest in the northern states for African Americans (data missing for many states) consistent with the pattern of solar UVB doses in summer [77,78,83].

In an analysis of race and 25(OHD) levels in relation to risk of death due to colorectal cancer [84], a significant two-fold increase in risk was seen among both non-Hispanic white and non-Hispanic black participants when comparing those with 25(OHD) levels less than 20 ng/mL to those with higher levels. Further, adjustment for vitamin levels accounted for almost half of the excess risk of colorectal cancer seen for black compared with white participants. In a recent systematic review and meta-analysis of 11 observational studies involving 7718 patients with CRC, overall survival was 32% greater when comparing high with low levels of 25(OH)D [85]. Thus, substantial evidence suggests a benefit for vitamin D in reducing CRC incidence and mortality.

Bladder and kidney cancers. In a meta-analysis of four prospective studies and one case–control study [86], the risk of urinary bladder cancer was 32% higher when comparing low versus high 25(OH)D level (risk ratio = 1.32 (95% confidence interval (CI), 1.15 to 1.89)). In a meta-analysis of two prospective cohort studies and seven nested case-control studies involving 130,609 participants who developed 1815 cases of kidney cancer, the highest 25(OH)D levels were associated with a significant 21% lower incidence (OR = 0.79, (95% CI, 0.69 to 0.91)) of kidney cancer [87].

Prostate cancer. In contrast to other cancers, higher 25(OH)D levels have been associated with a modestly higher risk of prostate cancer in prospective studies. A meta-analysis of 19 prospective cohort or nested case-control studies with a total of 35,583 participants and 12,786 prostate cancer cases found that higher 25(OH)D level was associated with increased prostate cancer relative risk = 1.15 (95% CI 1.02 to 1.06) [88].

On the other hand, a meta-analysis of six cohorts of 7648 patients with prostate cancer, for prostate cancer-specific mortality the hazard ratio for high vs. low 25(OH)D was 0.91 (95% CI: 0.88–0.95) for prediagnosis studies and 0.84 (95% CI: 0.58–1.21) for postdiagnosis serum levels [89]. In a case–control study, African-American men with a higher intake of vitamin D had a lower risk of total and aggressive prostate cancer; these associations were not seen in European men [90].

Breast cancer. In a meta-analysis of cohort studies, women with higher versus lower baseline serum levels of 25(OH)D had a barely significant 8% lower incidence of breast cancer [91]; the inverse association was limited to premenopausal women. However, in a pooled analysis of cohort studies with 10,353 cases of breast cancer, standardized serum levels of 25(OH)D were not associated with risk of breast cancer overall or by menopausal status.

There was also no statistically significant difference by race (P for heterogeneity = 0.90). For the same increment in 25(OH)D levels, the RR was 0.98 (CI, 0.95 to 1.02) in whites (9,579 cases); 1.28 (CI, 0.99 to 1.65) in blacks (290 cases); and 1.13 (CI, 0.76 to 1.68) in Asians (275 cases) [92]. In a cohort of 59,000 African-American women, predicted serum 25(OH)D levels (based on sun exposure, dietary intake, adiposity, and other variables) were inversely associated with risk of breast cancer (1454 cases): risk was 23% higher for the lowest versus the highest quintile [93]. In a recent case–control study among black women, daylight hours spent outdoors per year was inversely associated with lower risk of breast cancer [94].

Total cancer: The VITAL Randomized Trial. In the large VITAL trial [95] participants were randomized to 2000 IU of vitamin D per day and followed for five years. Although vitamin D was interpreted to have no significant overall effect on total cancer incidence, the incidence among African Americans was reduced by 23% (HR = 0.77 (95% CI, 0.59 to 1.01, p = 0.06)). Further, after excluding the first two years of follow-up as part of the planned analysis, total cancer mortality was significantly (p <0.05) reduced by 25% (HR = 0.75 (95% CI, 0.59 to 0.96)) among all participants.

Notably, the inclusion of participants with a relatively high baseline serum 25(OH)D level (mean = 31 ng/mL), many of whom also took supplementary vitamin D, plus the limited duration of follow-up, may have obscured benefits of vitamin D for cancer incidence. In a recent meta-analysis of ten RCTs including VITAL, no benefit of vitamin D supplementation was seen for cancer incidence (6537 cases) [96]. However, cancer mortality was reduced by 13% (95% CI, 4% to 21%) in the five available trials (1591 deaths). In another secondary analysis, there was a significant reduction in advanced cancers (metastatic or fatal) for those randomized to vitamin D compared with placebo [97].

Thus, the findings from randomized trials support vitamin D supplementation for reducing cancer mortality among all participants and cancer incidence among African Americans.

reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913332/

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More information: The American Academy of Family Physicians