vitamin D and lower colon cancer risk

There are no compelling randomized controlled trials finding that adequate vitamin D levels are associated with reduced risk of colon cancer. However, a multitude of observational studies have confirmed this association, and a recent international pooling project of 17 cohorts reinforced its likely benefit (see vit d and colon cancer jnci2018 in dropbox, or doi: 10.1093/jnci/djy087).

Details:
-- participant-level data from 17 cohorts analyzed, with 5706 colorectal cancer cases and 7107 controls
-- these prospective court studies were from the United States (11), Europe (5), and Asia (1)
-- 51% were women, 84% white. Median age was 60. Median time from blood draw to diagnosis of cancer was 5.5 years.
-- Median circulating 25(OH)D levels in controls was 56 nmol/L (22 ng/mL): 54 nmol/L in women and 58 nmol/L in men
-- seasonally-adjusted medians range from 27.6% lower to 41.9% higher than the original 25(OH)D checked

Results:
-- compared with 25(OH)D levels of 50 to <62.5 nmol/L (20-25 ng/mL), considered to be sufficient by the Institute of Medicine for bone health (all of the following numbers used the fully-adjusted model as noted below):
    -- deficient 25(OH)D <30 nmol/L (12 ng/mL) was associated with 31% higher colorectal cancer risk, RR 1.31 (1.05-1.62)
    -- above sufficient 25(OH)D of 75-87.5 nmol/L (30-35 ng/mL) was associated with a 19% decreased risk, RR 0.81 (0.67-0.99)
    -- higher levels 25(OH)D of 87.5-100 nmol/L (35-40 ng/mL) were associated with a 27% decreased risk, RR equals 0.73 (0.59-0.91)
    -- 25(OH)D levels higher than 100 nmol/L (40 ng/mL) did not show further decline and was in fact cancer was not statistically significantly reduced [though small numbers of people in this group]
-- associations were minimally affected in the fully-adjusted model: adjusting for BMI, physical activity, or other risk factors (family history of colorectal cancer, alcohol consumption, smoking status, aspirin and NSAID use, menopausal status and hormone therapy in women), though dietary factors including calcium, fiber, folate, red and processed meats “were considered but had negligible impact on results and were therefore not included in the final model”.
-- for each 25 nmol/L (10 ng/mL) increment in circulating 25(OH)D levels, colorectal cancer was reduced 19% in women (p<0.001) and 7% in men (not statistically significant in men, p=0.20)
-- these associations between 25(OH)D levels and cancer were inverse in all subgroups including by colorectal cancer subsite, geographic region, and season of blood collection, though the association appears stronger for proximal vs distal colon cancer (but not statistically significant)

Commentary:
-- vitamin D does have several potential anticancer effects: it is anti-proliferative, pro-apoptotic, and anti-angiogenic. There are vitamin D receptors throughout the body, and they have documented effects on both the innate and adaptive immune systems (which could potentially affect cancer development). Vitamin D receptors in particular are  located in the large bowel, and there are local factors in the colon which affect the synthesis and degradation of 1,25(OH)₂D, the active form of vitamin D that affects gene transcription, including the expression of the APC gene (adenomatous  polyposis coli gene)
-- The few randomized controlled trials to date on vitamin D and colorectal cancer have mostly not shown statistically significant effects. For example the Women’s Health Initiative randomized women to 1000 mg elemental calcium plus 400 IU of vitamin D, finding no effect on invasive cancers, but this study was limited by the low dose of vitamin D given, limited adherence to the vitamin, not checking serum 25(OH)D levels both before and after supplementation, and there were only 322 colorectal cancers diagnosed (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403703/ ). There are several ongoing RCTs which may help illuminate the benefit of vitamin D supplementation. However,  a very recent RCT from Nebraska of women with already high 25(OH)D levels of 82 nmol/L (32.8 ng/ml), which increased with vitamin D supplementation to 110 nmol/L (43.9 ng/mL), found a very-close-to-statistically-significant (p=0.06) decrease in new diagnosis of cancer after only 4 years. and they found even more benefit at 138 nmol/L (55 ng/mL) over 75 nmol/L (30 ng/mL), with 35% less cancer (see  http://gmodestmedblogs.blogspot.com/2018/04/vitamin-d-and-cancer-rct.html )
-- One interesting aspect of the pooling study was the difference between women and men in vitamin D benefit. It turns out that a reanalysis of the Women’s Health Initiative above did find a lower risk of colorectal cancer but only in women not receiving exogenous estrogen, suggesting an interplay between estrogen and vitamin D
-- the current study had the benefit of looking at actual circulating serum 25(OH)D levels and the subsequent development of colorectal cancer, not done in many other studies.
-- of interest, the association between high vitamin D levels and decreased colon cancer tended to no more for proximal lesions, which tend to have a worse prognosis when detected by colonoscopy (see discussion in http://gmodestmedblogs.blogspot.com/2018/01/aspirin-prevents-colon-cancer.html )
-- not sure what to make of the lack of effect of very high 25(OH)D levels, though only 3.5% of patients had levels greater than 100 nmol/L, making risk estimates imprecise
-- advantages of the study were its ability to get participant-level data, enough information to develop seasonally adjusted 25(OH)D levels, and a consistent and widely accepted 25(OH)D assay was used across the studies
-- limitations of the study include the fact that there was only a single blood draw for 25(OH)D levels, there was relatively limited racial/ethnic diversity, and as a compilation of observational studies it cannot determine causality (were those with higher 25(OH)D levels doing more healthful behaviors that were not accounted for in the individual studies, and it was these other healthful behaviors that lowered the colon cancer risk???)

So, this international pooling project does provide some impressive evidence of the association with higher vitamin D levels and reduced risk of colon cancer, especially since there was a pretty clear consistency in the methodology of the studies from many different countries, and there was a pretty clear dose-response curve with higher amounts of vitamin D being associated with increasingly lower risk. It also may be that the appropriate 25(OH)D levels to decrease the risk of colon cancer is higher than that for bone health, at 75-100 nmol/L (30-40 ng/mL), and perhaps even higher as in the Nebraska study above.

As suggested in many prior blogs, there does seem to be an array of potentially positive effects of adequate vitamin D levels (almost all cells in the body have vitamin D receptors), vitamin D levels track with latitude/sun exposure and are not associated with the usual healthy behaviors of diet and exercise, and there really is not much downside to taking a supplement in areas or in specific patients with inadequate sun exposure.

also, see http://gmodestmedblogs.blogspot.com/2018/04/vitamin-d-and-cancer-risk-cohort-study.html , a recent long-term prospective Japanese study finding decreased overall cancer risk with increasing 25(OH)D levels​. their achieved 25(OH)D levels were much lower than in the Nebraska study (the highest quartile in the Japanese study was 29 ng/mL), and they found a leveling off of benefit in the 23-29 ng/mL range 

and, http://gmodestmedblogs.blogspot.com/search/label/vitamin%20d  for many prior vitamin D blogs (including ones on heart disease, infections -- esp TB, statin myopathy, respiratory diseases.....)

geoff​

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