The review by Sperati and colleagues concluded that “vitamin D use seems not to be associated with a reduced risk of breast cancer development in postmenopausal women”. [1]. However, the authors noted that the trials examined had significant limitations. It was also mentioned in the introduction that evidence from prospective studies of serum 25-hydroxyvitamin D [25(OH)D] level and breast cancer risk remains substantially unclear.

I will address four topics in my commentary:
1 – whether the vitamin D randomized controlled trials (RCTs) for reducing risk of breast cancer were properly conducted;
2 – whether observational studies support the role of vitamin D in reducing risk of breast cancer incidence and death; and
3 – whether the evidence that solar ultraviolet-B (UVB) irradiance and vitamin D can be considered causally linked to reduced risk of breast cancer incidence and mortality.

1. Conducting vitamin D RCTs.
RCTs with nutritional supplements are generally based on the model for pharmaceutical drugs in that they give specified amounts and look for effects. The problem with this approach for vitamin D is that people have different serum 25(OH)D levels, and there are different changes in serum 25(OH)D level for given oral intakes [2]. The proper way to conduct such studies is to start with a serum 25(OH)D level-health outcome relation, enroll people with serum 25(OH)D levels near the low end of the relation, supplement with sufficient vitamin D to raise serum 25(OH)D levels to the upper end, and measure serum 25(OH)D levels after supplementation [3]. The Women’s Health Initiative study [4] did not follow any of these guidelines. The Creighton University study did measure serum 25(OH)D levels at time of enrollment and after one year of supplementation [5], but enrolled women near the upper end of the serum 25(OH)D level-breast cancer incidence relation [6]. The RECORD Trial measured serum 25(OH)D levels in a subset of the participants, finding a mean serum 25(OH)D level at time of enrollment of 38 nmol/l but did not measure serum 25(OH)D levels after supplementation [7].

One RCT reanalysis overlooked was that by Bolland and colleagues [8]. While it did not qualify for inclusion in their analysis since the study looked at the combined supplementation of vitamin D plus calcium, it illustrates the concerns raised in Ref. 3. It was a reanalysis of the Women’s Health Initiative Study [4]. For women not taking and personal vitamin D or calcium supplements prior to enrolling in the study, for total breast cancer, taking vitamin D plus calcium resulted in a hazard ratio was 0.82 (95% confidence interval, 0.70-0.97, p=0.021). For invasive breast cancer, the hazard ratio was 0.80 (95% confidence interval, 0.66-0.96, p=0.015). In women taking personal calcium or vitamin D supplements, supplementation with vitamin D and calcium did not alter cancer risk (HR: 1.06-1.26).

2. Observational studies
Observational studies of serum 25(OH)D level and breast cancer incidence rates are generally of two types, case-control studies and nested case-control studies derived from cohort studies. In the former, the serum 25(OH)D level is determined near the time of cancer diagnosis, while in the latter, it is determined at time of enrollment, which may precede diagnosis by several years. Case-control studies agree well with each other [9-13]. A graphical meta-analysis of the findings from these studies finds a robust serum 25(OH)D level-breast cancer incidence relation, with rapid reduction in risk for increases from low serum 25(OH)D levels and modest changes with increases in serum 25(OH)D level above 75 nmol/l [6]. The results were similar for premenopausal [11] and postmenopausal women [10].

As noted by Sperati and colleagues [1], nested case-control studies generally do not show a beneficial effect of serum 25(OH)D in reducing risk of breast cancer. The reason is that breast cancer is a rapidly developing cancer and serum 25(OH)D levels change with season and time in general. In fact, there is a global seasonality of breast cancer incidence rates, with highest rates in spring and fall [14]. The authors proposed that vitamin D reduces growth of breast cancer in summer, while melatonin does so in winter. The effect of follow-up time on observational studies of breast cancer incidence rates was discussed in a recent paper [15]. Only studies with less than a three-year follow-up period reported a significant inverse relation between serum 25(OH)D level and breast cancer incidence rate. However, for colon cancer, such relations were found out to follow-up times of 12 years.

Case-control studies are considered to have the possible bias of “reverse causation”, i.e., that the disease state may affect the biological parameters. This is thought not to be the case for serum 25(OH)D level and breast cancer incidence rates for two reasons. First, women generally do not know they have breast cancer until it is discovered, such as through routine mammography, so are unlikely to change UVB irradiance or any oral intake. Second, in a comparison of relative risk of breast cancer incidence with respect to serum 25(OH)D level vs. years of follow up, the findings for the case-control studies were on the linear fit to the findings from cohort studies [15].

Observational studies have also found that higher serum 25(OH)D levels are associated with better survival after diagnosis of breast cancer [16, 17].

3 – Does the evidence support a causal role of UVB and vitamin D in reducing risk of breast cancer?
While the medical model of causality is primarily based on RCTs, the scientific model of causality includes many more factors. A good set of criteria for causality in a biological system was proposed by A. Bradford Hill [18]. The primary criteria for causality that apply to UVB and vitamin D and breast cancer include strength of association, consistent findings in different populations, temporality, biological gradient, plausibility (e.g., mechanisms), experiment (e.g., RCTs), and analogy. These criteria have been examined for breast cancer and found to be largely satisfied [19-21].

In summary, RCTs to date have not established that vitamin D reduces the risk of breast cancer. However, evidence from ecological, case-control observational, and laboratory studies strongly support the role of UVB irradiance and vitamin D in reducing risk of breast cancer and increasing survival rates after diagnosis. Hopefully well-conducted RCTs will eventually agree.

References
1.Sperati F, Vici P, Maugeri-Saccà M, Stranges S, Santesso N, Mariani L, et al. Vitamin d supplementation and breast cancer prevention: a systematic review and meta-analysis of randomized clinical trials. PLoS One. 2013;8(7):e69269.
2. Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 2011;31:617-22.
3. Lappe JM, Heaney RP. Why randomized controlled trials of calcium and vitamin D sometimes fail. Dermatoendocrin. 2012;4(2):95-100.
4. Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O’Sullivan MJ, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684–96.
5. 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.
6. Grant WB. A review of the evidence regarding the solar ultraviolet-B–vitamin D–cancer hypothesis. Standardy Medyczne/Pediatria. 2012;9:610-9.
7. Avenell A, Maclennan GS, Jenkinson DJ, McPherson GC, McDonald AM, Pant PR, et al. Long-Term Follow-Up for Mortality and Cancer in a Randomized Placebo-Controlled Trial of Vitamin D3 and/or Calcium (RECORD Trial). J Clin Endocrinol Metab. 2012;97(2):614-622.
8. 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.
9. Lowe LC, Guy M, Mansi JL, Peckitt C, Bliss J, Wilson RG, et al. Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population. Eur J Cancer. 2005;41(8):1164-9.
10. Abbas S, Linseisen J, Slanger T, Kropp S, Mutschelknauss E, Flesch-Janys D, et al. Serum 25-hydroxyvitamin D and risk of postmenopausal breast cancer - results of a large case-control study. Carcinogenesis. 2008;29(1):93-9.
11. Abbas S, Chang-Claude J, Linseisen J. Plasma 25-hydroxyvitamin D and premenopausal breast cancer risk in a German case-control study. Int J Cancer. 2009;124(1):250-5.
12. Crew KD, Gammon MD, Steck SE, Hershman DL, Cremers S, Dworakowski E, et al. Association between plasma 25-hydroxyvitamin D and breast cancer risk. Cancer Prev Res (Phila Pa). 2009;2(6):598-604.
13. Fedirko V, Torres-Mejía G, Ortega-Olvera C, Biessy C, Angeles-Llerenas A, Lazcano-Ponce E, Saldaña-Quiroz VA, 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. 2012;23(7):1149-1162.
14. Oh EY, Ansell C, Nawaz H, Yang CH, Wood PA, Hrushesky WJ. Global breast cancer seasonality. Breast Cancer Res Treat. 2010;123(1):233-43.
15. 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(3):199-204.
16. Grant WB, Peiris AN. Differences in vitamin D status may account for unexplained disparities in cancer survival rates between African and White Americans. Dermatoendocrinol. 2012;4(2):85-94.
17. Tretli S, Schwartz GG, Torjesen PA, 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. 2012;23(2):363-70.
18. Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965 May;58:295-300.
19. Grant WB. How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer? An examination using Hill’s criteria for causality. Dermatoendocrinol. 2009;1(1):17-24.
20. Mohr SB, Gorham ED, Alcaraz JE, Kane CI, Macera CA, Parsons JE, et al. Does the evidence for an inverse relationship between serum vitamin D status and breast cancer risk satisfy the Hill criteria? Dermatoendocrin. 2012;4(2):152-7.
21. Grant WB. A review of evidence that ultraviolet-B irradiance and vitamin D reduce risk for cancer. US Endocrinology. 2013;9(1):50-54