Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-based Prospective Study cohortBMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k671 (Published 07 March 2018) Cite this as: BMJ 2018;360:k671
All rapid responses
The follow-up period between blood draw and cancer incidence was too long to expect significant findings for individual cancers
The prospective study on cancer incidence in Japan with respect to serum 25-hydroxyvitamin D [25(OH)D] concentration at baseline (1) has some interesting findings, but is hampered by two systemic problems: the long follow-up period (15.9-yr median) and the fact that Japan underwent a nutrition transition from the traditional Japanese diet to the Western diet between about 1965 and 1995 (2).
Serum 25(OH)D concentrations change in time due to seasonal variations in solar UVB doses, changes in time spent out of doors, diet, and age. Elderly adults are less efficient at producing vitamin D from UVB exposure due to reduced 7-dehydroxycholesterol in the skin (3). Thus, the longer the follow-up period, the lower the probability that baseline 25(OH)D concentration will be the concentration associated with cancer incidence. This effect has been demonstrated for breast and colorectal cancer (4) and all-cause mortality rate (5).
The effect of the nutrition transition in Japan has been to increase the prevalence of dementia (2) and colorectal cancer (6) with a lag time of about 20 years after the changes. For dementia, rates increased in an approximately linear manner from 1985 to 2008, overlapping significantly with the period of the study in Ref. 1. Thus, dietary changes could have overwhelmed effects of vitamin D for several of the cancers linked to Western diets such as colorectal and breast cancers.
Regarding the statement in the paper, "Despite the strong ecological and experimental animal evidence, however, evidence linking circulating concentration of vitamin D to the overall cancer risk in humans is sparse and inconsistent.", many of the studies referenced were flawed either by long follow-up periods or by poor clinical trial design (7). However, inspection of those with strong designs, there is strong support for the vitamin D-cancer hypothesis. For breast cancer, case-control studies in which 25(OH)D concentration was measured near the time of cancer diagnosis show a strong inverse correlation between 25(OH)D concentration and cancer incidence (4, 8). Breast cancer develops rapidly so that studies with follow-up periods longer than three years seldom find significant inverse correlations. See, also, the pooled analysis of cancer incidence with respect to serum 25(OH)D concentration by McDonnell et al. (9).
Three clinical trials also provide strong support for the vitamin D-cancer hypothesis (10-12). A reanalysis of the Women's Health Initiative found that "In 15,646 women (43%) who were not taking personal calcium or vitamin D supplements at randomization, CaD significantly decreased the risk of total, breast, and invasive breast cancers by 14-20% and nonsignificantly reduced the risk of colorectal cancer by 17%. In women taking personal calcium or vitamin D supplements, CaD did not alter cancer risk (HR: 1.06-1.26)." (8). Since those in the treatment arm were given only 400 IU/d vitamin D3 plus 1000 mg/d calcium, these findings are exactly what would be expected based on the 25(OH)D concentration-breast cancer incidence relationship from case-control studies (7). The recent trial by Lappe et al. (9) in which the treatment group received 2000 IU/d of vitamin D3 and 1500 mg/d of calcium, found, based on intention to treat "A new diagnosis of cancer was confirmed in 109 participants, 45 (3.89%) in the vitamin D3 + calcium group and 64 (5.58%) in the placebo group (difference, 1.69% [95% CI, -0.06% to 3.46%]; P = 0.06)." However, the results of the analysis based on achieved 25(OH)D concentration found that those who achieved concentrations of 130-210 nmol/l had significantly reduced incidence of all-cancer compared to those with <70 nmol/l, as discussed in the online supplement. The authors were not permitted by the journal to discuss this analysis in the printed text since it was not included in the original trial protocol.
1. Budhathoki S, Hidaka A, Yamaji T, et al. Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-based Prospective Study cohort. BMJ. 2018;360:k671.
4. Grant WB. 25-Hydroxyvitamin D and breast cancer, colorectal cancer, and colorectal adenomas: case–control versus nested case–control studies, Anticancer Res. 2015;35(2):1153-60.
2. Grant WB. Trends in diet and Alzheimer’s disease during the nutrition transition in Japan and developing countries. J Alz Dis, 2014;38(3):611-20.
3. MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest. 1985;76(4):1536-8.
5. 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.
6. Kuriki K, Tajima K. The increasing incidence of colorectal cancer and the preventive strategy in Japan. Asian Pac J Cancer Prev. 2006;7(3):495-501.
7. Grant WB, Boucher BJ, Bhattoa, Lahore HJ. Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations. J Steroid Biochem Mol Biol. 2018;177:266-9.
8. Grant WB, Boucher BJ. Randomized controlled trials of vitamin D and cancer incidence: A modeling study. PLos One. 2017;12(5):e0176448.
9. McDonnell SL, Baggerly C, French CB, et al. Serum 25-hydroxyvitamin D concentrations ≥40 ng/ml are associated with >65% lower cancer risk: Pooled analysis of randomized trial and prospective cohort study. PLoS One. 2016;11(4):e0152441.
10. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85(6):1586-91.
11. Bolland MJ, Grey A, Gamble GD, Reid IR. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr. 2011;94(4):1144-9.
12. Lappe J, Watson P, Travers-Gustafson D, et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women: A randomized clinical trial. JAMA. 2017;317(12):1234-43.
Competing interests: I receive funding from Bio-Tech Phamacal, Inc. (Fayetteville, AR) and serve on the board of directors of the Vitamin D Council (San Luis Obispo, CA).
Re: Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-based Prospective Study cohort
To the Editor:
We read with great interest the study by Budhathoki et al, BMJ 2018;360:k671 (1), where the authors reported an association between plasma 25-hydroxyvitamin D levels and overall risk of developing cancer. Subgroup analyses showed significant associations especially in i) breast cancer in pre-menopausal women and ii) liver cancer. We believe that at least the latter finding should be interpreted with caution.
Vitamin D is metabolised in the liver into its major circulating form, 25-hydroxyvitamin D, which was evaluated in the abovementioned study (1). The foremost risk factor for developing hepatocellular carcinoma (the most common type of primary liver cancer in adults) is pre-existing cirrhosis, which often is considered a premalignant condition (2), justifying the recommendation of biannual surveillance by means of liver ultrasonography in hepatitis C virus (HCV) infected cirrhotic patients (3). Cirrhosis furthermore augments the risk of developing other malignancies (4).
As liver function declines in more advanced stages of liver fibrosis, especially in decompensated cirrhosis, the ability to metabolise vitamin D into 25-hydroxyvitamin D also is affected, leading to lower concentrations (5).
We previously performed a multicentre therapeutic trial among HCV genotype 2 or 3 infected patients (the NORDynamIC study) (6). A pre-treatment liver biopsy was mandatory and liver fibrosis was evaluated using the Ishak protocol, where fibrosis stage 0 indicates no fibrosis, 1-2 mild fibrosis, 3-4 bridging fibrosis, and 5-6 cirrhosis. In a post-hoc analysis, pre-treatment plasma concentrations of 25-hydroxyvitamin D were determined (Architect 25-hydroxyvitamin D assay, Abbot diagnostics). Cirrhotic patients (i.e. Ishak fibrosis stage 5-6) had significantly lower concentrations as compared to those among non-cirrhotic patients (mean 52 nmol/L ± 18 (SD) (n=43) vs. 60 nmol/L ± 23 (SD) (n=288) respectively, p=0.03 Student’s T-test). When dividing the patients according to quartiles based on 25-hydroxyvitamin D concentrations, as performed in the study by Budhathoki et al, we noted that 16 of 83 (19%) in 0-25th percentile, 11 of 83 (13%) in the 25th-50th percentile, 10 of 83 (12%) in the 50th-75th percentile and 6 of 82 (7%) in the 75th-100th percentile had cirrhosis, and the difference was significant when comparing the 0-25th and 75th-100th percentiles (p=0.04 Fisher’s exact test).
In light of these findings from the NORDynamIC trial, pre-existing cirrhosis should have been accounted for and discussed as a potential underlying confounding factor in the study by Budhathoki et al. Additionally, enhancing vitamin D concentrations without simultaneously attempting to ameliorate advanced stages of liver fibrosis may not lead to decreased risk of developing liver cancer.
1. Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014;21(3):319-29.
2. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(5 Suppl 1):S35-50.
3. Lagging M, Wejstal R, Duberg AS, Aleman S, Weiland O, Westin J, et al. Treatment of hepatitis C virus infection for adults and children: updated Swedish consensus guidelines 2017. Infect Dis (Lond). 2018:1-15.
4. Kalaitzakis E, Gunnarsdottir SA, Josefsson A, Bjornsson E. Increased risk for malignant neoplasms among patients with cirrhosis. Clin Gastroenterol Hepatol. 2011;9(2):168-74.
5. Arteh J, Narra S, Nair S. Prevalence of vitamin D deficiency in chronic liver disease. Dig Dis Sci. 2010;55(9):2624-8.
6. Lagging M, Langeland N, Pedersen C, Farkkila M, Buhl MR, Morch K, et al. Randomized comparison of 12 or 24 weeks of peginterferon alpha-2a and ribavirin in chronic hepatitis C virus genotype 2/3 infection. Hepatology. 2008;47(6):1837-45.
Competing interests: No competing interests
The work of Budhathoki et al. is methodologically robust and their findings make an important contribution to the current literature (1). However it is prematrue and indeed a non-sequitur to conclude that vitamin D has an oncoprotective effect.
Their study shows a strong inverse correlation between serum vitamin D and the risk of a host of cancers. However, in contrast with this finding, the body of evidence from the most recent 2014 Cochrane review and randomised controlled trials shows that vitamin D supplementation does not reduce the risk of cancer (2,3,4). One must conclude that vitamin D is a surrogate or proxy for an oncoprotector, given that its putative protective effect against cancer is not reproduced by vitamin D supplementation.
The authors correctly identify that their study population do not consume significant quantities of food fortified with vitamin D, hence the majority of their vitamin is photogenerated. UV light itself may be the oncoprotector. UV light produces nascent tumour cells in the skin, with generic tumour antigens involved in tumorigenesis and metastases. These cells are eradicated by the host immmunity, resulting in some acquired immunity to future tumour antigens and cancer. This is solar vaccination. Vitamin D levels are a surrogate marker for UV exposure, hence the associations observed by the authors. Thus UV light may be the oncoprotector rather than vitamin D.
One of the most telling pieces of evidence is that of Dimitrakopoulou, published in this journal (5). They uncouple vitamin D levels from UV exposure, to see if there is a veritable link with vitamin D and cancer risk. The authors look at inviduals with low vitamin D levels due to genetic polymorphisms. However, these individuals had no increased risk of 7 cancer types. Similar results have been reported in the context of individual cancers such as prostate cancer (6,7). These studies conclude that the a causal link can not explain any relationship between vitamin D and tumour risk. Hence the evidence does not appear to support the authors' conclusion in this present study that the inverse association of serum vitamin D levels with cancer risk is suggestive of an anti-tumour effect of vitamin D.
(1) Budhathoki SS, Hidaka A, Yamaji T, Sawada N, Tanaka-Mizuno S, Kuchiba A, Charvat H, Goto A, Kojima S, Sudo N, Shimazu T, Sasazuki S, Inoue M, Tsugane S, Iwasaki M; Japan Public Health Center-based Prospective Study Group. Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-based Prospective Study cohort. BMJ. 2018 Mar 7;360:k671
(2) Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Krstic G, Wetterslev J, Gluud C.Vitamin D supplementation for prevention of cancer in adults. Cochrane Database Syst Rev. 2014 Jun 23;(6):CD007469
(3) Manson JE, Bassuk SS, Buring JE.Vitamin D, Calcium, and Cancer: Approaching Daylight? JAMA. 2017 Mar 28;317(12):1217-1218
(4) Lappe J, Watson P, Travers-Gustafson D, Recker R, Garland C, Gorham E, Baggerly K, McDonnell SL.Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women: A Randomized Clinical Trial. JAMA. 2017 Mar 28;317(12):1234-1243.
(5) Dimitrakopoulou VI, Tsilidis KK, Haycock PC, et al. Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study. BMJ2017;359:j4761
(6) Trummer O, Langsenlehner U, Krenn-Pilko S, Pieber TR, Obermayer-Pietsch B, Gerger A, Renner W, Langsenlehner T.Vitamin D and prostate cancer prognosis: a Mendelian randomization study. World J Urol. 2016 Apr;34(4):607-11. doi: 10.1007/s00345-015-1646-9. Epub 2015 Jul 25.
(7) Mondul AM, Shui IM, Yu K, Travis RC, Stevens VL, Campa D, Schumacher FR, Ziegler RG, Bueno-de-Mesquita HB, Berndt S, Crawford ED, Gapstur SM, Gaziano JM, Giovannucci E, Haiman CA, Henderson BE, Hunter DJ, Johansson M, Key TJ, Le Marchand L, Lindström S, McCullough ML, Navarro C, Overvad K, Palli D, Purdue M, Stampfer MJ, Weinstein SJ, Willett WC, Yeager M, Chanock SJ, Trichopoulos D, Kolonel LN, Kraft P, Albanes D.Genetic variation in the vitamin d pathway in relation to risk of prostate cancer--results from the breast and prostate cancer cohort consortium. Cancer Epidemiol Biomarkers Prev. 2013 Apr;22(4):688-96
Competing interests: No competing interests
* Ronald Coase.
Budhathokiet al’s evaluation of the association between pre-diagnostic circulating vitamin D concentration and the subsequent risk of cancers deserves robust comment.(1)
First, using arbitrary cut-points to derive various subgroups (by quarter and by third) for vitamin D is not appropriate as there is a continuous distribution of the values with no obvious modal values.
Second, similarly for arbitrary cut-points to derive subgroups for confounding clinical variables. Moreover, a self-administered survey is a poorly reliable method for variables such as tobacco or alcohol use.
Accordingly, the sophistication of the statistical methods for adjustment contrasts with the poor quality and relevance of the data. However, the main problem is that adjustment is almost impossible: a) smokers have lower vitamin D;(2) b) vitamin D is associated with a higher risk of tobacco-related cancers.(3) Similarly, alcohol consumption, obesity, insulin resistance, type 2 diabetes have an impact on vitamin D status.(4)
In 1998, a robust prospective survey (NHANES III, n= 13,331) investigated vitamin D levels with mortality, accounting for age, sex, ethnicity, diabetes, current smoking, body mass index, physical activity, supplementation, season.(5) It revealed a small higher risk, which was not statistically significant. More recent well-designed studies are also negative as recently a nested case-control study from the Prostate, Lung, Colorectal, and Ovarian Cancer screening trial cohort which failed to show evidence that vitamin D plays a protective role.(6) In this study controls were matched to each case by age, race, sex, and month of blood draw while Budhathoki et al created complex and unvalidated quantiles to account for seasonal variability.(1)
Age-specific mortality rate of cancer is increasing in Japan. Obviously infection and tobacco use ranks first for causality; if other causes or risk factors deserve scrutiny, it must be food borne mutagenic/carcinogenic heterocyclic amines.(7)
1 Budhathoki S, Hidaka A, Yamaji T et al. Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-basedProspective Study cohort. BMJ 2018;360:k671.
2 Tønnesen R, Hovind PH, Jensen LT, Schwarz P. Determinants of vitamin D status in young adults: influence of lifestyle, sociodemographic and anthropometric factors. BMC Public Health 2016;16:385.
3 Afzal S, Bojesen SE, Nordestgaard BG. Low plasma 25-hydroxyvitamin D and risk of tobacco-related cancer. Clin Chem 2013;59:771-80.
4 Palaniswamy S, Hyppönen E, Williams D, Jokelainen J, Lowry E, Keinänen-Kiukaanniemi S, Herzig KH, Järvelin MR, Sebert S. Potential determinants of vitamin D in Finnish adults: a cross-sectional study from the Northern Finland birth cohort 1966. BMJ Open 2017;7: e013161.
5 Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008;168:1629-37.
6 Piper MR, Freedman DM, Robien K et al. Vitamin D-binding protein and pancreatic cancer: a nested case-control study. Am J Clin Nutr 2015;101:1206-15.
7 Nagao M, Tsugane S. Cancer in Japan: Prevalence, prevention and the role of heterocyclic amines in human carcinogenesis. Genes Environ 2016; 38: 16.
Competing interests: No competing interests