Letters to the Editor

95% CIs decrease, it would also be worthwhile to perform the calculations for 1, 2, 3, and up to 13 y of follow-up. Note that baseline 25(OH)D concentrations were found to be inversely correlated with incidence and mortality rates for hepatocellular and renal cell carcinoma in other European prospective studies (8, 9).

Dear Editor:

The author receives funding from Bio-Tech Pharmacal (Fayetteville, AR) and the Vitamin D Council (San Luis Obispo, CA).

The recent article by Khaw et al. (1) found that baseline 25hydroxyvitamin D [25(OH)D] concentration was significantly inversely correlated with mortality from all-cause, cardiovascular, and respiratory disease but not with cancer. In addition, 25(OH)D concentrations were significantly inversely correlated with incidence of cardiovascular and respiratory disease, but at a less significant level than for mortality rates, as well as all fracture events. This finding is consistent with other studies reporting that vitamin D appears to have a stronger effect on mortality rates than incidence rates (2). Given that there is strong evidence for beneficial effects of solar UV-B on cancer incidence and mortality rates from ecological studies (3), as well as from observational studies for breast and colorectal cancer (4), the findings in this study for cancer seem to require further investigation. A possible explanation for the cancer finding is that the long follow-up time obscured the effect of 25(OH)D concentrations on incidence and mortality rates and that some of the cancers are not sensitive to vitamin D. The effect of long follow-up time was discussed in 2 articles in which it was shown that the longer the follow-up time, the smaller the observed effect or 25(OH)D concentration (5, 6). The effect of follow-up time is especially strong for breast cancer, which has rapidly developing tumors, and after 3 y of follow up it is very difficult to find a significant inverse correlation with respect to baseline 25(OH)D concentration (5). Case-control studies, in which the 25(OH)D concentration is measured at the time of diagnosis, always find a significant inverse correlation between baseline 25(OH)D concentration and breast cancer incidence rate. Evidence that breast cancer develops rapidly includes that mammography is recommended annually and that breast cancer has a marked seasonal variation in diagnosis, with higher rates in spring and fall (7). The sensitivity of cancer to vitamin D depends on the type of cancer, and not all cancers are vitamin D sensitive. For example, there is limited evidence that lung cancer incidence and mortality rates are inversely correlated with solar UV-B doses or vitamin D (3). Khaw et al. (1) reported that the fully adjusted HR for all-cause mortality rate excluding deaths at 5 y was 0.94 (95% CI: 0.89, 0.98) compared with 0.92 (95% CI: 0.86, 0.93) for all deaths. In a calculation that takes into account the number of deaths at 5 y (n ¼ 641), the estimated HR for the all-cause mortality rate for the first 5 y would be 0.87 (95% CI: 0.81, 0.94). Assuming the same ratio of cancer deaths at 5 y gives an HR for cancer mortality rates of 0.89 (95% CI: 0.80, 0.99), which is significant. Thus, it would be worthwhile for the authors to perform this calculation properly as well to look at the types of cancer involved in their study. Because the HR very likely approaches 1.0 as follow-up time increases, whereas the

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William B Grant From the Sunlight, Nutrition, and Health Research Center, San Francisco, CA (e-mail: [email protected]).

REFERENCES 1. Khaw KT, Luben R, Wareham N. Serum 25-hydroxyvitamin D, mortality, and incident cardiovascular disease, respiratory disease, cancers, and fractures: a 13-y prospective population study. Am J Clin Nutr 2014;100: 1361–70. 2. Grant WB, Garland CF. Vitamin D has a greater impact on cancer mortality rates than cancer incidence rates. BMJ 2014;348:g2862. 3. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients 2013;5:3993–4021. 4. Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B 2010;101:130–6. 5. 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;3:199–204. 6. Grant WB. Effect of follow-up time on the relation between prediagnostic serum 25-hydroxyitamin D and all-cause mortality rate. Dermatoendocrinol 2012;4:198–202. 7. Oh EY, Ansell C, Nawaz H, Yang CH, Wood PA, Hrushesky WJ. Global breast cancer seasonality. Breast Cancer Res Treat 2010;123:233–43. 8. Fedirko V, Duarte-Salles T, Bamia C, Trichopoulou A, Aleksandrova K, Trichopoulos D, Trepo E, Tjønneland A, Olsen A, Overvad K, et al. Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: a nested case-control study. Hepatology 2014;60:1222–30. 9. Muller DC, Fanidi A, Midttun O, Steffen A, Dossus L, Boutron-Ruault MC, Severi G, K¨uhn T, Katzke V, de la Torre RA, et al. Circulating 25hydroxyvitamin D3 in relation to renal cell carcinoma incidence and survival in the EPIC cohort. Am J Epidemiol 2014;180:810–20. doi: 10.3945/ajcn.114.102129.

Reply to WB Grant Dear Editor: We agree that total cancers are heterogeneous conditions and analyzing them as a group may obscure possible associations of individual

Am J Clin Nutr 2015;102:230–1. Printed in USA. Ó 2015 American Society for Nutrition

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Long follow-up time and different sensitivities of cancer types may have obscured the effect of 25-hydroxyvitamin D on cancer incidence and mortality rates

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LETTERS TO THE EDITOR

Kay-Tee Khaw Robert Luben Nicholas Wareham From the Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom (RL; K-TS, e-mail: [email protected]), and the MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom (NW).

REFERENCE

None of the authors had any conflicts of interests.

1. Khaw KT, Luben R, Wareham N. Serum 25-hydroxyvitamin D, mortality, and incident cardiovascular disease, respiratory disease, cancers, and fractures: a 13-y prospective population study. Am J Clin Nutr 2014;100: 1361–70. doi: 10.3945/ajcn.114.102962.

TABLE 1 HRs (95% CIs) for cancer mortality and cancer incidence by follow-up time per 20-nmol/L increase in serum 25(OH)D in 14,614 men and women in EPIC Norfolk, 1997–20121 Deaths Follow-up time 2y Age, sex, and month adjusted Multivariable adjusted2 4y Age, sex, and month adjusted Multivariable adjusted2 6y Age, sex, and month adjusted Multivariable adjusted2 8y Age, sex, and month adjusted Multivariable adjusted2 10 y Age, sex, and month adjusted Multivariable adjusted2 Final Age, sex, and month adjusted Multivariable adjusted2 1

Cancer incidence

HR (95% CI)

P

No. of events

HR (95% CI)

P

86

0.80 (0.65, 0.99) 0.84 (0.65, 1.08)

0.04 0.016

387

0.93 (0.84, 1.02) 0.92 (0.83, 1.03)

0.11 0.16

234

0.82 (0.72, 0.93) 0.82 (0.71, 0.96)

0.002 0.01

788

0.96 (0.90, 1.02) 0.95 (0.88, 1.02)

0.18 0.14

364

0.91 (0.82, 1.00) 0.93 (0.83, 1.04)

0.06 0.18

1174

0.98 (0.93, 1.03) 0.98 (0.93, 1.05)

0.35 0.61

560

0.93 (0.86, 1.00) 0.94 (0.86, 1.03)

0.06 0.18

1594

0.97 (0.93, 1.03) 0.98 (0.93, 1.03)

0.19 0.42

744

0.93 (0.86, 0.99) 0.93 (0.86, 1.01)

0.03 0.08

1974

0.99 (0.95, 1.03) 0.99 (0.95, 1.04)

0.48 0.71

1086

0.93 (0.88, 0.99) 0.94 (0.89, 1.00)

0.017 0.07

3121

1.01 (0.97, 1.04) 1.02 (0.99, 1.06)

0.77 0.21

No. of events

EPIC, European Prospective Investigation into Cancer and Nutrition; 25(OH)D, 25-hydroxyvitamin D. Adjusted for age, sex, month, BMI, cigarette smoking, alcohol intake, plasma vitamin C, physical activity, diabetes, history of cardiovascular disease, history of cancer, social class, and educational level. 2

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cancers with 25-hydroxyvitamin D [25(OH)D] concentrations (1). However, space constraints did not allow us to examine the associations with individual cancers in detail and to discuss this issue adequately. We note Grant’s comments about the duration of follow-up. Table 1 below shows the HRs per increase of 20 nmol/L in serum 25(OH)D concentration for total cancer mortality and incidence according to follow-up time. There is indeed some support for somewhat lower HRs for mortality due to cancer with shorter follow-up time, such that the lowest significant HRs were observed for the 2- and 4-y follow-up, as hypothesized by Grant, and a trend at the 10- and 13-y follow-up. The cancer incidence data showed no statistical significance or trends with follow-up time. We agree that cancer is heterogeneous, and we will indeed be examining in more detail the associations between the incidence of individual cancers with 25(OH)D.

Reply to WB Grant.

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