Review ArticleClinical StudiesR

25-Hydroxyvitamin D and Breast Cancer, Colorectal Cancer, and Colorectal Adenomas: Case–Control versus Nested Case–Control Studies

WILLIAM B. GRANT
Anticancer Research February 2015, 35 (2) 1153-1160;

Abstract

Background: Existing literature includes concerns regarding reliability of case–control studies of breast cancer incidence with respect to 25-hydroxyvitamin D (25(OH)D) concentrations. For breast cancer, only case–control studies consistently find inverse correlations between 25(OH)D and breast cancer. However, for colorectal cancer, nested case–control studies find significant inverse correlations with respect to 25(OH)D concentrations at baseline for mean follow-up times of 7 years. Materials and Methods: This is a review of results currently existing in literature. Results: I provide evidence that 25(OH)D concentration values are only useful for short follow-up times for breast cancer since it develops rapidly. To support the robust nature of breast cancer case–control studies, I show that results from 11 studies from seven countries align in a robust power-law fit to the odds ratio versus mean 25(OH)D concentrations. Conclusion: Case–control studies of breast cancer incidence rates provide reliable results.

The role of solar ultraviolet-B (UVB) irradiance and vitamin D in reducing breast cancer risk was hypothesized in 1989-90 (1-3). Many ecological, observational, and laboratory studies and randomized controlled trials (RCTs) have since examined solar UVB and vitamin D in reducing breast cancer risk and increasing survival. Ecological studies have found significant inverse correlations between solar UVB indices and incidence and/or mortality rates of breast cancer in Australia, China, France, Nordic countries, Spain, and the United States (4). Case–control studies have found significant inverse correlations between 25-hydroxyvitamin D (25(OH)D) concentrations and breast cancer incidence (5); however, nested case–control studies from cohort studies have not, as discussed in several meta-analyses (6-12). This divergence has given rise to concern that reverse causality might affect case–control studies – i.e., that disease state affects 25(OH)D concentrations. Studies have associated higher 25(OH)D concentrations at diagnosis with improved prognosis (13, 14). The mechanisms whereby vitamin D reduces risk of breast cancer and increases survival are well-known, including effects on cellular differentiation and proliferation, angiogenesis, and metastasis (4). Two RCTs of vitamin D plus calcium support vitamin D's role in reducing breast cancer risk (15, 16). Solar UVB and vitamin D satisfy Hill's criteria for causality in a biological system for breast cancer (17). Yet, since nested case–control studies do not support the UVB–vitamin D–breast cancer hypothesis and since RCTs are considered weak, the scientific community has not widely accepted the role of UVB and vitamin D in reducing cancer risk.

This article explores reasons for the difference between case–control and nested case–control studies of breast cancer incidence with respect to 25(OH)D concentrations.

Materials and Methods

The present article updates two earlier studies. One addresses how follow-up time affects incidence of breast and colorectal cancer (18). The other is on the 25(OH)D concentration–breast cancer incidence relation based on case–control studies (5).

Table I gives data for the breast cancer incidence rates used to examine how follow-up time affects relative risk (RR).

The data are primarily for the same studies as in Table II of an earlier paper (18). The RR ratios or odds ratios (ORs) are for a change in 25(OH)D concentration of 50 nmol/L, as calculated in another paper (7), except for two additional studies, for which changes were easy to determine. One study gave the OR for a continuous variation (29). Another gave ORs for five ethnic groups with approximately equal case and control groups (106 to 229) (11), which were then averaged. From the original papers, I either obtained the mean years of follow-up before breast cancer diagnosis or estimated the value as half the total follow-up period. Some confusion was present in my previous paper (18) regarding whether “follow-up time” meant follow-up time or mean follow-up time before cancer diagnosis.

Table II gives median 25(OH)D concentration quantiles as well as RRs for these values for breast cancer case–control studies.

For colorectal cancer, I obtained RR values for an increase of 50 nmol/L for several studies from a meta-analysis (35). I obtained data from three additional studies from the original papers (36-38). Table III gives the data used.

Data for colorectal adenomas came from Tables I and II in Appendix B of a meta-analysis (7). The case–control studies included those by Levine and colleagues (44), Peters and colleagues (45), Fedirko and colleagues (46), and Takahashi and colleagues (47). The nested case–control studies included those by Platz and colleagues (48), Peters and colleagues (49), and Jacobs and colleagues (50). The data set included one randomized, double-blind, placebo-controlled trial (51) and one cross-sectional study (52).

I used KaleidaGraph 4.02 (Synergy Software, Reading, PA, USA) to graph data for OR versus mean 25(OH)D concentration for the quantiles.

Results

For both case–control and nested case–control studies, Figure 1 plots RRs with 95% confidence intervals (CIs) for breast cancer incidence for a 50-nmol/L increase in 25(OH)D concentration against years of mean follow-up to diagnosis. The linear regression fit to the RR had the form RR=0.57+0.10 year, r=0.84.

Figure 2 shows OR versus mean or median value of 25(OH)D concentration quantiles for breast cancer case–control studies. The data were fit with a power law, OR=18.5×[25(OH)D]−0.837, R=0.90. Rapid change in OR is evident from 15 to 40 nmol/L, a moderate change from 40 to 80 nmol/L, and then little change thereafter. Showing remarkable consistency in their relation, Figure 2 consists of data from 11 studies from seven countries.

Figure 3 plots RRs with 95% CIs for colorectal cancer for a 50-nmol/L increase against years of follow-up. The linear fit to the RR had the form RR=0.45+0.039 year, r=0.34.

Figure 4 shows case–control studies of colorectal adenoma with respect to 25(OH)D concentration. All but one, (49) for men, had an inverse correlation. Figure 5 is the same as Figure 4 except that it is for the nested case–control studies; randomized double-blind, placebo-controlled trial; and cross-sectional studies. Three studies had direct correlations with 25(OH)D: one with 6 years of follow-up (48), one with 1 and 4 years (51), and one with unspecified follow-up (49).

Discussion

This review again shows that case–control studies of 25(OH)D concentration and breast cancer incidence have different outcomes from those of nested case–control studies. I present evidence that the difference occurs because breast cancer develops rapidly, so that within a short period –generally less than the follow-up time of nested case-control studies– the 25(OH)D concentration measured at enrollment loses predictive value. Two earlier papers of mine made this point. Both showed that for breast and colorectal cancer and all-cause mortality rate, the longer the follow-up time, the less likely that a significant finding would exist–and, if so, the OR was reduced (18, 53). In the present study, slopes of RR for cancer incidence with respect to years of follow-up, the ratio for breast cancer to colorectal cancer was 0.10/0.039, or a factor of 2.6 times. This ratio does not translate directly to a difference in tumor growth rates but is probably related to that difference.

View this table:
Table I.

Data for breast cancer incidence as a function of mean follow-up time to diagnosis.

A study from Denmark offers evidence that 25(OH)D concentrations can change significantly over moderate intervals at the population level. This article examined the relation between 25(OH)D concentration at enrollment in a cohort study and incidence of cancer (54). Mean serum 25(OH)D levels for like-age populations decreased from 65 nmol/L in 1993-94 to 52 nmol/L in 1999-2001 and 44 nmol/L in 2006-08 (Table II) (54).

At least two reasons exist to consider that breast cancer tumors develop faster than other tumors do, e.g. colorectal. For one, breast cancer has a seasonal variation in detection rates, being highest in spring and fall (55). The authors of that study hypothesized that vitamin D production in summer and melatonin production in winter could explain the findings. A second reason is that the American Cancer Society recommends mammographic screening every year for women older than 40 years but only every 5-10 years for colorectal cancer (56).

I consider colorectal adenomas here because they can progress to colorectal cancer (albeit only 5%) (57), which has the strongest evidence for the role of solar UVB and vitamin D in reducing risk (58). The comparison with colorectal adenomas also supports the hypothesis that case–control studies yield useful results. Four out of the five case–control studies showed significant inverse correlations between 25(OH)D concentration, whereas only four of the seven other studies did. The authors of one meta-analysis expressed no concern that their study included four case–control studies, five nested case–control studies, and two cross-sectional studies (59).

View this table:
Table II.

Data for breast cancer case–control studies.

A meta-analysis of nested case–control studies separating findings between pre-menopause and post-menopause found no significant correlation for breast cancer risk versus 25(OH)D concentration for premenopausal women. But it did find a significantly reduced risk for postmenopausal women with 25(OH)D concentration of 35 ng/mL (RR=0.81 [95% CI=0.69-0.96], p=0.01) and 40 ng/mL (RR=0.83 [95%CI=0.71-0.97], p=0.02) (8).

Further evidence that vitamin D reduces breast cancer risk comes from ecological studies of breast cancer incidence and/or mortality rate with respect to geographical variation of solar UVB doses. Boscoe and colleagues inversely correlated breast cancer incidence rates with solar UVB doses in the U.S. (60). Ecological studies also inversely correlated with an index of outdoor work in a study of cancer incidence in Nordic countries (61). A study in China found that breast cancer incidence rates directly correlated with solar UVB doses, whereas mortality rates correlated inversely (62). Breast cancer mortality rates inversely correlated with solar UVB doses in Australia (63), China (62), France (64), Japan (65), Spain (66), and the U.S. (3, 60, 67, 68). Many of these studies adjusted findings with respect to other cancer risk–modifying factors. Increasing evidence indicates that vitamin D is more effective at reducing cancer progression than incidence (69, 70).

As to whether solar UVB's only benefit on risk of cancer is through vitamin D production, a recent paper found that other, not yet identified mechanisms exist whereby UV irradiance reduces cancer progression. In a mouse model of intestinal tumor growth, mice with 25(OH)D concentrations raised to 62±31 nmol/L by UVB irradiance (VD−/UV+) had significantly fewer adenocarcinomas and lower mean area per tumor than mice with 25(OH)D concentrations raised to 75±15 nmol/L via oral vitamin D (VD+/UV−) and controls (VD−/UV−) with 25(OH)D concentrations of 8 nmol/L (71). However, VD+/UV− mice had only slightly lower numbers and areas of adenocarcinomas than VD−/UV− mice. This finding suggests that ecological studies of UVB doses and cancer incidence and mortality rates may only partly relate to vitamin D production. The original UVB–vitamin D–cancer hypothesis was based on the assumption that vitamin D production was the most important physiological effect of solar irradiance (72).

View this table:
Table III.

Data for colorectal cancer as a function of mean follow-up time to diagnosis.

One concern regarding the case–control studies is that people with more advanced breast cancer may have lower 25(OH)D concentrations. However, the same findings would seem to be made for nested case–control studies of breast cancer or colorectal cancer as well. Therefore, this concern seems not to affect the difference between breast cancer case–control and nested case–control studies. Another concern is that disease state may affect 25(OH)D concentration (reverse causality). This concern is unlike for certain reasons. One is that women diagnosed with breast cancer are generally unaware of having it until so diagnosed, so they are unlikely to change sun exposure or vitamin D intake habits before diagnosis. Also, little or no evidence exists that breast cancer affects 25(OH)D concentrations per se.

Figure 1.
Figure 1.

Plot of RR for breast cancer incidence versus mean follow-up period with linear regression fits.

Observational studies of breast cancer mortality rates with respect to 25(OH)D concentrations also support vitamin D's role in reducing breast cancer risk. A meta-analysis of 25(OH)D concentrations at diagnosis found that high versus low25(OH)D concentrations were significantly associated with lower breast cancer mortality (pooled RR=0.58 [95% CI=0.40-0.85]) and overall mortality (pooled RR=0.61 [95% CI=0.48-0.79]) (12). Four studies included regarded breast cancer–specific mortality (13, 73-75). The six studies regarding all-cause mortality rate included those four plus Goodwin and colleagues and Jacobs and colleagues (76, 77).

RCTs offer some evidence for a beneficial effect of vitamin D in reducing breast cancer risk. An RCT of postmenopausal women in Nebraska divided subjects into three arms–placebo, 1,450 mg/d calcium, and 1,450 mg/d calcium plus 1,100 IU/d vitamin D3. Between the ends of the first and fourth years, the RR was 0.23 (95% CI=0.09-.60; p<0.005),whereas that for the calcium-only arm was 0.40 (p=0.01) (15). In the Women's Health Initiative study, “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)” (16).

Figure 2.
Figure 2.

Plot of OR or RR for breast cancer incidence versus mean 25(OH)D concentration of quantiles for 11 case–control studies from seven countries. Original OR or RR values were multiplied by factors to bring them into agreement along the power-law regression fit.

Figure 3.
Figure 3.

Plot of RR for colorectal cancer incidence versus mean follow-up period with linear regression fits.

Figure 4.
Figure 4.

Plot of ORs for colorectal adenoma versus mean values of 25(OH)D concentrations for quantiles for case–control studies.

No other vitamin D RCTs have shown a beneficial effect on cancer rates, although they may have been poorly-designed and conducted. Such RCTs have been largely based on the pharmaceutical model, which assumes that the agent in the trial is the only source of the agent and that a linear dose–response relation exists between agent and health outcome. Neither assumption is valid for vitamin D trials. Robert Heaney recently proposed guidelines for nutritional studies that apply to vitamin D (78): 1. Start with an understanding of the 25(OH)D concentration–health outcome relation. 2. Measure 25(OH)D concentrations of prospective trial participants and include only those with 25(OH)D concentrations near the low-end of the relation. 3. Supplement with enough vitamin D3 to raise 25(OH)D concentrations to near the upper end of the relation. 4. Remeasure 25(OH)D concentrations. 5. Ensure that important cofactors are optimized.

Few vitamin D RCTs followed these guidelines. RCTs that found significant benefits of vitamin D supplementation were more likely to be conducted on people with low 25(OH)D concentrations. Dark skin pigmentation or low solar UVB irradiance (for example, caused by clothing styles or staying indoors when sick) accounted for these low concentrations. Fifty percent of trials conducted on populations with mean baseline 25(OH)D concentrations below 48 nmol/L found beneficial effects on biomarkers of inflammation, while only 20% of those with 25(OH)D concentration above 52 nmol/L, a value typical of many populations, did (Cannell, Grant, and Holick, manuscript in review). The study by Lappe and colleagues (15) is an exception. The re-analysis by Bolland (16) shows the importance of low baseline 25(OH)D concentration for a successful trial.

Figure 5.
Figure 5.

Same as Figure 4 but for other types of studies.

Conclusion

The evidence and analysis presented herein support the hypothesis that both case–control and nested case–control studies are appropriate for colorectal cancer studies but that only case–control studies of breast cancer accurately and reliably determine the 25(OH)D concentration–breast cancer incidence relation, whereas nested case–control studies with mean follow-up times longer than 3 years prior to diagnosis do not. The reason for the difference is that breast cancer develops much faster than colorectal cancer, so baseline 25(OH)D concentrations lose predictive ability fairly quickly. Thus, breast cancer should join colorectal cancer as significantly reduced by higher 25(OH)D concentrations in addition to greater solar UVB irradiance.

Footnotes

  • Disclosure

    I receive funding from Bio-Tech Pharmacal (Fayetteville, AR), the Sunlight Research Forum (Veldhoven), and Medi-Sun Engineering, LLC (Highland Park, IL).

  • Received August 26, 2014.
  • Revision received October 5, 2014.
  • Accepted October 10, 2014.

References

  1. ↵
    1. Colston KW,
    2. Berger U,
    3. Coombes RC
    : Possible role for vitamin D in controlling breast cancer cell proliferation. Lancet 1(8631): 188-191, 1989.
    OpenUrlPubMed
    1. Garland CF,
    2. Comstock GW,
    3. Garland FC,
    4. Helsing KJ,
    5. Shaw EK,
    6. Gorham ED
    : Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet 2(8673): 1176-1178, 1989.
    OpenUrlPubMed
  3. ↵
    1. Garland FC,
    2. Garland CF,
    3. Gorham ED,
    4. Young JF
    : Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med 19(6): 614-622, 1990.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Moukayed M,
    2. Grant WB
    : Molecular link between vitamin D and cancer prevention. Nutrients 5(10): 3993-4021, 2013.
    OpenUrlCrossRefPubMed
  5. ↵
    1. Grant WB
    : The role of animal products and vitamin D in risk of breast cancer. Nutr Clin Pract 28(1): 140, 2013.
    OpenUrlFREE Full Text
  6. ↵
    1. Gandini S,
    2. Boniol M,
    3. Haukka J,
    4. Byrnes G,
    5. Cox B,
    6. Sneyd MJ,
    7. Mullie P,
    8. Autier P
    : Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int J Cancer 128(6): 1414-1424, 2011.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Yin L,
    2. Grandi N,
    3. Raum E,
    4. Haug U,
    5. Arndt V,
    6. Brenner H
    : Meta-analysis: serum vitamin D and breast cancer risk. Eur J Cancer 46(12): 2196-2205, 2010.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Bauer SR,
    2. Hankinson SE,
    3. Bertone-Johnson ER,
    4. Ding EL
    : Plasma vitamin D levels, menopause, and risk of breast cancer: dose-response meta-analysis of prospective studies. Medicine (Baltimore) 92(3): 123-131, 2013.
    OpenUrlCrossRefPubMed
    1. Chen P,
    2. Li M,
    3. Gu X,
    4. Liu Y,
    5. Li X,
    6. Li C,
    7. Wang Y,
    8. Xie D,
    9. Wang F,
    10. Yu C,
    11. Li J,
    12. Chen X,
    13. Chu R,
    14. Zhu J,
    15. Ou Z,
    16. Wang H
    : Higher blood 25(OH)D level may reduce the breast cancer risk: evidence from a Chinese population based case-control study and meta-analysis of the observational studies. PLoS One 8(1): e49312, 2013.
    OpenUrlPubMed
    1. Wang D,
    2. Velez de-la-Paz OI,
    3. Zhai JX,
    4. Liu DW
    : Serum 25-hydroxyvitamin D and breast cancer risk: a meta-analysis of prospective studies. Tumour Biol 34(6): 3509-3517, 2013.
    OpenUrlPubMed
  11. ↵
    1. Kim Y,
    2. Franke AA,
    3. Shvetsov YB,
    4. Wilkens LR,
    5. Cooney RV,
    6. Lurie G,
    7. Maskarinec G,
    8. Hernandez BY,
    9. Le Marchand L,
    10. Henderson BE,
    11. Kolonel LN,
    12. Goodman MT
    : Plasma 25-hydroxyvitamin D3 is associated with decreased risk of postmenopausal breast cancer in whites: a nested case-control study in the multiethnic cohort study. BMC Cancer 14: 29, 2014.
    OpenUrlPubMed
  12. ↵
    1. Kim Y,
    2. Je Y
    : Vitamin D intake, blood 25(OH)D levels, and breast cancer risk or mortality: a meta-analysis. Br J Cancer 110(11): 2772-2784, 2014.
    OpenUrlPubMed
  13. ↵
    1. Tretli S,
    2. Schwartz GG,
    3. Torjesen PA,
    4. Robsahm TE
    : Serum levels of 25-hydroxyvitamin D and survival in Norwegian patients with cancer of breast, colon, lung, and lymphoma: a population-based study. Cancer Causes Control 23(2): 363-370, 2012.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Toriola AT,
    2. Nguyen N,
    3. Scheitler-Ring K,
    4. Colditz GA
    : Circulating 25-hydroxyvitamin D levels and prognosis among cancer patients: a systematic review. Cancer Epidemiol Biomarkers Prev 23(6): 917-933, 2014.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Lappe JM,
    2. Travers-Gustafson D,
    3. Davies KM,
    4. Recker RR,
    5. Heaney RP
    : Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 85(6): 1586-1591, 2007.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Bolland MJ,
    2. Grey A,
    3. Gamble GD,
    4. 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 94(4): 1144-1149, 2011.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Mohr SB,
    2. Gorham ED,
    3. Alcaraz JE,
    4. Kane CI,
    5. Macera CA,
    6. Parsons JK,
    7. Wingard DL,
    8. Garland CF
    : Does the evidence for an inverse relationship between serum vitamin D status and breast cancer risk satisfy the Hill criteria? Dermatoendocrinol 4(2): 152-157, 2012.
    OpenUrlPubMed
  18. ↵
    1. Grant WB
    : An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr 65(9): 1016-1026, 2011.
    OpenUrlCrossRefPubMed
    1. Lowe LC,
    2. Guy M,
    3. Mansi JL,
    4. Peckitt C,
    5. Bliss J,
    6. Wilson RG,
    7. Colston KW
    : Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population. Eur J Cancer 41(8): 1164-1169, 2005.
    OpenUrlCrossRefPubMed
    1. Abbas S,
    2. Linseisen J,
    3. Slanger T,
    4. Kropp S,
    5. Mutschelknauss EJ,
    6. Flesch-Janys D,
    7. Chang-Claude J
    : Serum 25-hydroxyvitamin D and risk of post-menopausal breast cancer – results of a large case-control study. Carcinogenesis 29(1): 93-99, 2008.
    OpenUrlAbstract/FREE Full Text
    1. Abbas S,
    2. Chang-Claude J,
    3. Linseisen J
    : Plasma 25-hydroxyvitamin D and premenopausal breast cancer risk in a German case-control study. Int J Cancer 124(1): 250-255, 2009.
    OpenUrlCrossRefPubMed
    1. Crew KD,
    2. Shane E,
    3. Cremers S,
    4. McMahon DJ,
    5. Irani D,
    6. Hershman DL
    : High prevalence of vitamin D deficiency despite supplementation in premenopausal women with breast cancer undergoing adjuvant chemotherapy. J Clin Oncol 27(13): 2151-2156, 2009.
    OpenUrlAbstract/FREE Full Text
    1. Yao S,
    2. Sucheston LE,
    3. Millen AE,
    4. Johnson CS,
    5. Trump DL,
    6. Nesline MK,
    7. Davis W,
    8. Hong CC,
    9. McCann SE,
    10. Hwang H,
    11. Kulkarni S,
    12. Edge SB,
    13. O'Connor TL,
    14. Ambrosone CB
    : Pretreatment serum concentrations of 25-hydroxyvitamin D and breast cancer prognostic characteristics: a case-control and a case-series study. PLoS One 6(2): e17251, 2011.
    OpenUrlCrossRefPubMed
    1. Rejnmark L,
    2. Tietze A,
    3. Vestergaard P,
    4. Buhl L,
    5. Lehbrink M,
    6. Heickendorff L,
    7. Mosekilde L
    : Reduced prediagnostic 25-hydroxyvitamin D levels in women with breast cancer: a nested case-control study. Cancer Epidemiol Biomarkers Prev 18(10): 2655-2660, 2009.
    OpenUrlAbstract/FREE Full Text
    1. Bertone-Johnson ER,
    2. Chen WY,
    3. Holick MF,
    4. Hollis BW,
    5. Colditz GA,
    6. Willett WC,
    7. Hankinson SE
    : Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 14(8): 1991-1997, 2005.
    OpenUrlAbstract/FREE Full Text
    1. McCullough ML,
    2. Stevens VL,
    3. Patel R,
    4. Jacobs EJ,
    5. Bain EB,
    6. Horst RL,
    7. Gapstur SM,
    8. Thun MJ,
    9. Calle EE
    : Serum 25-hydroxyvitamin D concentrations and postmenopausal breast cancer risk: a nested case control study in the Cancer Prevention Study-II Nutrition Cohort. Breast Cancer Res 11(4): R64, 2009.
    OpenUrlCrossRefPubMed
    1. Chlebowski RT
    : Vitamin D and breast cancer incidence and outcome. Anticancer Agents Med Chem 13(1): 98-106, 2013.
    OpenUrlPubMed
    1. Freedman DM,
    2. Chang SC,
    3. Falk RT,
    4. Purdue MP,
    5. Huang WY,
    6. McCarty CA,
    7. Hollis BW,
    8. Graubard BI,
    9. Berg CD,
    10. Ziegler RG
    : Serum levels of vitamin D metabolites and breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 17(4): 889-894, 2008.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Kuhn T,
    2. Kaaks R,
    3. Becker S,
    4. Eomois PP,
    5. Clavel-Chapelon F,
    6. Kvaskoff M,
    7. Dossus L,
    8. Tjonneland A,
    9. Olsen A,
    10. Overvad K,
    11. Chang-Claude J,
    12. Lukanova A,
    13. Buijsse B,
    14. Boeing H,
    15. Trichopoulou A,
    16. Lagiou P,
    17. Bamia C,
    18. Masala G,
    19. Krogh V,
    20. Sacerdote C,
    21. Tumino R,
    22. Mattiello A,
    23. Buckland G,
    24. Sanchez MJ,
    25. Menendez V,
    26. Chirlaque MD,
    27. Barricarte A,
    28. Bueno-de-Mesquita HB,
    29. van Duijnhoven FJ,
    30. van Gils CH,
    31. Bakker MF,
    32. Weiderpass E,
    33. Skeie G,
    34. Brustad M,
    35. Andersson A,
    36. Sund M,
    37. Wareham N,
    38. Khaw KT,
    39. Travis RC,
    40. Schmidt JA,
    41. Rinaldi S,
    42. Romieu I,
    43. Gallo V,
    44. Murphy N,
    45. Riboli E,
    46. Linseisen J
    : Plasma 25-hydroxyvitamin D and the risk of breast cancer in the European prospective investigation into cancer and nutrition: a nested case-control study. Int J Cancer 133(7): 1689-1700, 2013.
    OpenUrlPubMed
    1. Fedirko V,
    2. Torres-Mejia G,
    3. Ortega-Olvera C,
    4. Biessy C,
    5. Angeles-Llerenas A,
    6. Lazcano-Ponce E,
    7. Saldana-Quiroz VA,
    8. Romieu I
    : Serum 25-hydroxyvitamin D and risk of breast cancer: results of a large population-based case-control study in Mexican women. Cancer Causes Control 23(7): 1149-1162, 2012.
    OpenUrlCrossRefPubMed
    1. Peppone LJ,
    2. Rickles AS,
    3. Janelsins MC,
    4. Insalaco MR,
    5. Skinner KA
    : The association between breast cancer prognostic indicators and serum 25-OH vitamin D levels. Ann Surg Oncol 19(8): 2590-2599, 2012.
    OpenUrlPubMed
    1. Bilinski K,
    2. Boyages J
    : Association between 25-hydroxyvitamin D concentration and breast cancer risk in an Australian population: an observational case-control study. Breast Cancer Res Treat 137(2): 599-607, 2013.
    OpenUrlPubMed
    1. Mohr SB,
    2. Gorham ED,
    3. Alcaraz JE,
    4. Kane CI,
    5. Macera CA,
    6. Parsons JK,
    7. Wingard DL,
    8. Horst R,
    9. Garland CF
    : Serum 25-hydroxyvitamin D and breast cancer in the military: a case-control study utilizing pre-diagnostic serum. Cancer Causes Control 24(3): 495-504, 2013.
    OpenUrlCrossRefPubMed
    1. Yousef FM,
    2. Jacobs ET,
    3. Kang PT,
    4. Hakim IA,
    5. Going S,
    6. Yousef JM,
    7. Al-Raddadi RM,
    8. Kumosani TA,
    9. Thomson CA
    : Vitamin D status and breast cancer in Saudi Arabian women: case-control study. Am J Clin Nutr 98(1): 105-110, 2013.
    OpenUrlAbstract/FREE Full Text
  35. ↵
    1. Yin L,
    2. Grandi N,
    3. Raum E,
    4. Haug U,
    5. Arndt V,
    6. Brenner H
    : Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk. Aliment Pharmacol Ther 30(2): 113-125, 2009.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Yaylim-Eraltan I,
    2. Arzu Ergen H,
    3. Arikan S,
    4. Okay E,
    5. Ozturk O,
    6. Bayrak S,
    7. Isbir T
    : Investigation of the VDR gene polymorphisms association with susceptibility to colorectal cancer. Cell Biochem Funct 25(6): 731-737, 2007.
    OpenUrlCrossRefPubMed
    1. Woolcott CG,
    2. Wilkens LR,
    3. Nomura AM,
    4. Horst RL,
    5. Goodman MT,
    6. Murphy SP,
    7. Henderson BE,
    8. Kolonel LN,
    9. Le Marchand L
    : Plasma 25-hydroxyvitamin D levels and the risk of colorectal cancer: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev 19(1): 130-134, 2010.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Jenab M,
    2. Bueno-de-Mesquita HB,
    3. Ferrari P,
    4. van Duijnhoven FJ,
    5. Norat T,
    6. Pischon T,
    7. Jansen EH,
    8. Slimani N,
    9. Byrnes G,
    10. Rinaldi S,
    11. Tjonneland A,
    12. Olsen A,
    13. Overvad K,
    14. Boutron-Ruault MC,
    15. Clavel-Chapelon F,
    16. Morois S,
    17. Kaaks R,
    18. Linseisen J,
    19. Boeing H,
    20. Bergmann MM,
    21. Trichopoulou A,
    22. Misirli G,
    23. Trichopoulos D,
    24. Berrino F,
    25. Vineis P,
    26. Panico S,
    27. Palli D,
    28. Tumino R,
    29. Ros MM,
    30. van Gils CH,
    31. Peeters PH,
    32. Brustad M,
    33. Lund E,
    34. Tormo MJ,
    35. Ardanaz E,
    36. Rodriguez L,
    37. Sanchez MJ,
    38. Dorronsoro M,
    39. Gonzalez CA,
    40. Hallmans G,
    41. Palmqvist R,
    42. Roddam A,
    43. Key TJ,
    44. Khaw KT,
    45. Autier P,
    46. Hainaut P,
    47. Riboli E
    : Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study. BMJ 340: b5500, 2010.
    OpenUrlAbstract/FREE Full Text
    1. Wu-Wong JR,
    2. Nakane M,
    3. Ma J,
    4. Ruan X,
    5. Kroeger PE
    : VDR-mediated gene expression patterns in resting human coronary artery smooth muscle cells. J Cell Biochem 100(6): 1395-1405, 2007.
    OpenUrlCrossRefPubMed
    1. Tangrea J,
    2. Helzlsouer K,
    3. Pietinen P,
    4. Taylor P,
    5. Hollis B,
    6. Virtamo J,
    7. Albanes D
    : Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men. Cancer Causes Control 8(4): 615-625, 1997.
    OpenUrlCrossRefPubMed
    1. Feskanich D,
    2. Ma J,
    3. Fuchs CS,
    4. Kirkner GJ,
    5. Hankinson SE,
    6. Hollis BW,
    7. Giovannucci EL
    : Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 13(9): 1502-1508, 2004.
    OpenUrlAbstract/FREE Full Text
    1. Otani T,
    2. Iwasaki M,
    3. Sasazuki S,
    4. Inoue M,
    5. Tsugane S
    : Plasma vitamin D and risk of colorectal cancer: the Japan Public Health Center-Based Prospective Study. Br J Cancer 97(3): 446-451, 2007.
    OpenUrlCrossRefPubMed
    1. Wactawski-Wende J,
    2. Kotchen JM,
    3. Anderson GL,
    4. Assaf AR,
    5. Brunner RL,
    6. O'Sullivan MJ,
    7. Margolis KL,
    8. Ockene JK,
    9. Phillips L,
    10. Pottern L,
    11. Prentice RL,
    12. Robbins J,
    13. Rohan TE,
    14. Sarto GE,
    15. Sharma S,
    16. Stefanick ML,
    17. Van Horn L,
    18. Wallace RB,
    19. Whitlock E,
    20. Bassford T,
    21. Beresford SA,
    22. Black HR,
    23. Bonds DE,
    24. Brzyski RG,
    25. Caan B,
    26. Chlebowski RT,
    27. Cochrane B,
    28. Garland C,
    29. Gass M,
    30. Hays J,
    31. Heiss G,
    32. Hendrix SL,
    33. Howard BV,
    34. Hsia J,
    35. Hubbell FA,
    36. Jackson RD,
    37. Johnson KC,
    38. Judd H,
    39. Kooperberg CL,
    40. Kuller LH,
    41. LaCroix AZ,
    42. Lane DS,
    43. Langer RD,
    44. Lasser NL,
    45. Lewis CE,
    46. Limacher MC,
    47. Manson JE
    : Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 354(7): 684-696, 2006.
    OpenUrlCrossRefPubMed
  44. ↵
    1. Levine AJ,
    2. Harper JM,
    3. Ervin CM,
    4. Chen YH,
    5. Harmon E,
    6. Xue S,
    7. Lee ER,
    8. Frankel HD,
    9. Haile RW
    : Serum 25-hydroxyvitamin D, dietary calcium intake, and distal colorectal adenoma risk. Nutr Cancer. 39(1): 35-41, 2001.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Peters U,
    2. McGlynn KA,
    3. Chatterjee N,
    4. Gunter E,
    5. Garcia-Closas M,
    6. Rothman N,
    7. Sinha R
    : Vitamin D, calcium, and vitamin D receptor polymorphism in colorectal adenomas. Cancer Epidemiol Biomarkers Prev 10(12): 1267-1274, 2001.
    OpenUrlAbstract/FREE Full Text
  46. ↵
    1. Fedirko V,
    2. Bostick RM,
    3. Goodman M,
    4. Flanders WD,
    5. Gross MD
    : Blood 25-hydroxyvitamin D3 concentrations and incident sporadic colorectal adenoma risk: a pooled case-control study. Am J Epidemiol 172(5): 489-500, 2010.
    OpenUrlAbstract/FREE Full Text
  47. ↵
    1. Takahashi R,
    2. Mizoue T,
    3. Otake T,
    4. Fukumoto J,
    5. Tajima O,
    6. Tabata S,
    7. Abe H,
    8. Ohnaka K,
    9. Kono S
    : Circulating vitamin D and colorectal adenomas in Japanese men. Cancer Sci 101(7): 1695-1700, 2010.
    OpenUrlCrossRefPubMed
  48. ↵
    1. Platz EA,
    2. Hankinson SE,
    3. Hollis BW,
    4. Colditz GA,
    5. Hunter DJ,
    6. Speizer FE,
    7. Giovannucci E
    : Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and adenomatous polyps of the distal colorectum. Cancer Epidemiol Biomarkers Prev 9(10): 1059-1065, 2000.
    OpenUrlAbstract/FREE Full Text
  49. ↵
    1. Peters U,
    2. Hayes RB,
    3. Chatterjee N,
    4. Shao W,
    5. Schoen RE,
    6. Pinsky P,
    7. Hollis BW,
    8. McGlynn KA
    : Circulating vitamin D metabolites, polymorphism in vitamin D receptor, and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 13(4): 546-552, 2004.
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. Jacobs ET,
    2. Alberts DS,
    3. Benuzillo J,
    4. Hollis BW,
    5. Thompson PA,
    6. Martinez ME
    : Serum 25(OH)D levels, dietary intake of vitamin D, and colorectal adenoma recurrence. J Steroid Biochem Mol Biol 103(3-5): 752-756, 2007.
    OpenUrlCrossRefPubMed
  51. ↵
    1. Grau MV,
    2. Baron JA,
    3. Sandler RS,
    4. Haile RW,
    5. Beach ML,
    6. Church TR,
    7. Heber D
    : Vitamin D, calcium supplementation, and colorectal adenomas: results of a randomized trial. J Natl Cancer Inst 95(23): 1765-1771, 2003.
    OpenUrlAbstract/FREE Full Text
  52. ↵
    1. Silverman EB,
    2. Read RW,
    3. Boyle CR,
    4. Cooper R,
    5. Miller WW,
    6. McLaughlin RM
    : Histologic comparison of canine skin biopsies collected using monopolar electrosurgery, CO2 laser, radiowave radiosurgery, skin biopsy punch, and scalpel. Vet Surg 36(1): 50-56, 2007.
    OpenUrlPubMed
  53. ↵
    1. Grant WB
    : Re: “The influence of health and lifestyle characteristics on the relation of serum 25-hydroxyvitamin D with risk of colorectal and breast cancer in postmenopausal women”. Am J Epidemiol 176(9): 838, 2012.
    OpenUrlFREE Full Text
  54. ↵
    1. Skaaby T,
    2. Husemoen LL,
    3. Thuesen BH,
    4. Pisinger C,
    5. Jorgensen T,
    6. Roswall N,
    7. Larsen SC,
    8. Linneberg A
    : Prospective population-based study of the association between serum 25-hydroxyvitamin-D levels and the incidence of specific types of cancer. Cancer Epidemiol Biomarkers Prev 23(7): 1220-1229, 2014.
    OpenUrlAbstract/FREE Full Text
  55. ↵
    1. Oh EY,
    2. Ansell C,
    3. Nawaz H,
    4. Yang CH,
    5. Wood PA,
    6. Hrushesky WJ
    : Global breast cancer seasonality. Breast Cancer Res Treat 123(1): 233-243, 2010.
    OpenUrlPubMed
  56. ↵
    1. McAulay KA,
    2. Higgins CD,
    3. Macsween KF,
    4. Lake A,
    5. Jarrett RF,
    6. Robertson FL,
    7. Williams H,
    8. Crawford DH
    : HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection. J Clin Invest 117(10): 3042-3048, 2007.
    OpenUrlCrossRefPubMed
  57. ↵
    1. Carvalho B,
    2. Sillars-Hardebol AH,
    3. Postma C,
    4. Mongera S,
    5. Terhaar Sive Droste J,
    6. Obulkasim A,
    7. van de Wiel M,
    8. van Criekinge W,
    9. Ylstra B,
    10. Fijneman RJ,
    11. Meijer GA
    : Colorectal adenoma to carcinoma progression is accompanied by changes in gene expression associated with ageing, chromosomal instability, and fatty acid metabolism. Cell Oncol (Dordr) 35(1): 53-63, 2012.
    OpenUrlCrossRefPubMed
  58. ↵
    1. Giovannucci E
    : Epidemiology of vitamin D and colorectal cancer. Anticancer Agents Med Chem 13(1): 11-19, 2013.
    OpenUrlCrossRefPubMed
  59. ↵
    1. Wei MY,
    2. Garland CF,
    3. Gorham ED,
    4. Mohr SB,
    5. Giovannucci E
    : Vitamin D and prevention of colorectal adenoma: a meta-analysis. Cancer Epidemiol Biomarkers Prev 17(11): 2958-2969, 2008.
    OpenUrlAbstract/FREE Full Text
  60. ↵
    1. Boscoe FP,
    2. Schymura MJ
    : Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993-2002. BMC Cancer 6: 264, 2006.
    OpenUrlCrossRefPubMed
  61. ↵
    1. Grant WB
    : Role of solar UVB irradiance and smoking in cancer as inferred from cancer incidence rates by occupation in Nordic countries. Dermatoendocrinol 4(2): 203-211, 2012.
    OpenUrlPubMed
  62. ↵
    1. Chen W,
    2. Clements M,
    3. Rahman B,
    4. Zhang S,
    5. Qiao Y,
    6. Armstrong BK
    : Relationship between cancer mortality/incidence and ambient ultraviolet B irradiance in China. Cancer Causes Control 21(10): 1701-1709, 2010.
    OpenUrlCrossRefPubMed
  63. ↵
    1. Astbury A
    . Cancer mortality, cosmic ray neutron dose, and summer solar UV-B flux share similar geographical distributions in the USA.Triumf report TRI-PP-05-24. June 2005
  64. ↵
    1. Grant WB
    : Ecological studies of the UVB-vitamin D-cancer hypothesis. Anticancer Res 32(1): 223-236, 2012.
    OpenUrlAbstract/FREE Full Text
  65. ↵
    1. Mizoue T
    : Ecological study of solar radiation and cancer mortality in Japan. Health Phys 87(5): 532-538, 2004.
    OpenUrlCrossRefPubMed
  66. ↵
    1. Grant WB,
    2. Boucher BJ
    : Are Hill's criteria for causality satisfied for vitamin D and periodontal disease? Dermatoendocrinol 2(1): 30-36, 2010.
    OpenUrlCrossRefPubMed
  67. ↵
    1. Grant WB
    : An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 94(6): 1867-1875, 2002.
    OpenUrlCrossRefPubMed
  68. ↵
    1. Grant WB,
    2. Garland CF
    : The association of solar ultraviolet B (UVB) with reducing risk of cancer: multifactorial ecologic analysis of geographic variation in age-adjusted cancer mortality rates. Anticancer Res 26(4A): 2687-2699, 2006.
    OpenUrlAbstract/FREE Full Text
  69. ↵
    1. Chowdhury R,
    2. Kunutsor S,
    3. Vitezova A,
    4. Oliver-Williams C,
    5. Chowdhury S,
    6. Kiefte-de-Jong JC,
    7. Khan H,
    8. Baena CP,
    9. Prabhakaran D,
    10. Hoshen MB,
    11. Feldman BS,
    12. Pan A,
    13. Johnson L,
    14. Crowe F,
    15. Hu FB,
    16. Franco OH
    : Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ 348: g1903, 2014.
    OpenUrlAbstract/FREE Full Text
  70. ↵
    1. Grant WB,
    2. Garland CF
    : Vitamin D has a greater impact on cancer mortality rates than on cancer incidence rates. BMJ 348: g2862, 2014.
    OpenUrlFREE Full Text
  71. ↵
    1. Rebel H,
    2. der Spek CD,
    3. Salvatori D,
    4. van Leeuwen JP,
    5. Robanus-Maandag EC,
    6. de Gruijl FR
    : UV exposure inhibits intestinal tumor growth and progression to malignancy in intestine-specific Apc mutant mice kept on low vitamin D diet. Int J Cancer, 2014.
  72. ↵
    1. Garland CF,
    2. Garland FC
    : Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 9(3): 227-231, 1980.
    OpenUrlAbstract/FREE Full Text
  73. ↵
    1. Hatse S,
    2. Lambrechts D,
    3. Verstuyf A,
    4. Smeets A,
    5. Brouwers B,
    6. Vandorpe T,
    7. Brouckaert O,
    8. Peuteman G,
    9. Laenen A,
    10. Verlinden L,
    11. Kriebitzsch C,
    12. Dieudonne AS,
    13. Paridaens R,
    14. Neven P,
    15. Christiaens MR,
    16. Bouillon R,
    17. Wildiers H
    : Vitamin D status at breast cancer diagnosis: correlation with tumor characteristics, disease outcome, and genetic determinants of vitamin D insufficiency. Carcinogenesis 33(7): 1319-1326, 2012.
    OpenUrlAbstract/FREE Full Text
    1. Villasenor A,
    2. Ballard-Barbash R,
    3. Ambs A,
    4. Bernstein L,
    5. Baumgartner K,
    6. Baumgartner R,
    7. Ulrich CM,
    8. Hollis BW,
    9. McTiernan A,
    10. Neuhouser ML
    : Associations of serum 25-hydroxyvitamin D with overall and breast cancer-specific mortality in a multiethnic cohort of breast cancer survivors. Cancer Causes Control 24(4): 759-767, 2013.
    OpenUrlPubMed
  75. ↵
    1. Vrieling A,
    2. Seibold P,
    3. Johnson TS,
    4. Heinz J,
    5. Obi N,
    6. Kaaks R,
    7. Flesch-Janys D,
    8. Chang-Claude J
    : Circulating 25-hydroxyvitamin D and postmenopausal breast cancer survival: Influence of tumor characteristics and lifestyle factors? Int J Cancer 134(12): 2972-2983, 2014.
    OpenUrlPubMed
  76. ↵
    1. Goodwin PJ,
    2. Ennis M,
    3. Pritchard KI,
    4. Koo J,
    5. Hood N
    : Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer. J Clin Oncol 27(23): 3757-3763, 2009.
    OpenUrlAbstract/FREE Full Text
  77. ↵
    1. Jacobs ET,
    2. Thomson CA,
    3. Flatt SW,
    4. Al-Delaimy WK,
    5. Hibler EA,
    6. Jones LA,
    7. Leroy EC,
    8. Newman VA,
    9. Parker BA,
    10. Rock CL,
    11. Pierce JP
    : Vitamin D and breast cancer recurrence in the Women's Healthy Eating and Living (WHEL) Study. Am J Clin Nutr 93(1): 108-117, 2011.
    OpenUrlAbstract/FREE Full Text
  78. ↵
    1. Heaney RP
    : Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev 72(1): 48-54, 2014.
    OpenUrlCrossRefPubMed
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25-Hydroxyvitamin D and Breast Cancer, Colorectal Cancer, and Colorectal Adenomas: Case–Control versus Nested Case–Control Studies
WILLIAM B. GRANT
Anticancer Research Feb 2015, 35 (2) 1153-1160;
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