On 2015 Jan 15, William Grant commented:

Differences in 25-hydroxyvitamin D concentrations may explain Much of the black-white-Hispanic differences in breast cancer-specific survival in the United States

In the paper by Iqbal and colleagues, it was found that black women had higher probability of small-sized breast cancer tumors presenting with distant metastases than whites, as well as the highest proportion of triple-negative breast cancers [1]. Black women also had the highest hazard ratio for death for women with stage I breast cancer and tumors less than 2.0 cm in diameter, with Hispanic women having hazard ratios intermediate between those for blacks or whites. The conclusion, "Much of the difference could be statistically accounted for by intrinsic biological differences such as lymph node metastasis, distant metastasis, and triple-negative behavior of tumors." overlooked the fact that there might be explanations for these "intrinsic differences". In this comment, I outline the evidence that differences in 25-hydroxyvitamin D [25(OH)D] concentrations explain much of the findings.

First, there is strong evidence from geographical ecological studies that breast cancer mortality rates are inversely correlated with solar UVB doses [2]. Solar UVB is the primary source of vitamin D for most people. Since those with darker skin make vitamin D less efficiently than those with lighter skin, in the U.S., whites have the highest mean 25(OH)D concentrations, Hispanics intermediate concentrations, and blacks the lowest concentrations [3]. It was noted that these differences seem to explain the black-white cancer-specific and all-cause differences in survival after diagnosis of 13 types of cancer including breast cancer after consideration of socioeconomic status, stage at diagnosis, and treatment [4]. A recent review also found that higher 25(OH)D concentrations were significantly inversely correlated with breast cancer survival [5]. There is also strong evidence from case-control studies that breast cancer incidence is inversely correlated with 25(OH)D concentration [6, 7]. It is pointed out in that paper that nested case-control studies do not find significant inverse correlations because breast cancer tumors develop so rapidly that 25(OHD from blood drawn at the time of enrollment loses relevance as time increases.

Second, some of the findings noted in Ref. 1 are related to 25(OH)D concentrations. Those diagnosed with triple-negative breast cancer have been found to have lower 25(OH)D concentrations [8-10] and the actions of vitamin D on triple-negative breast cancer have been modeled [11].

While more research is required to fully understand the role of UVB and vitamin D in reducing risk of breast cancer and increasing survival after diagnosis, there is enough support for the role of vitamin D related to breast cancer that women who want reduce their risk of developing breast cancer and increase their chance of surviving after diagnosis should be advised to increase their 25(OH)D concentrations to above 75-100 nmol/L, which could take 1000-4000 IU/d vitamin D3 (cholecalciferol) in the absence of adequate UVB exposure [12]. Doing so would also have benefits for many other health outcomes [12].

References 1. Iqbal J, Ginsburg O, Rochon PA, Sun P, Narod SA. Differences in breast cancer stage at diagnosis and cancer-specific survival by race and ethnicity in the United States. JAMA. 2015;313(2):165-173. 2. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5(10):3993-4023. 3. Ginde AA, Liu MC, Camargo CA Jr. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med. 2009;169(6):626-32. 4. 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. 5. Mohr SB, Gorham ED, Kim J, Hofflich H, Garland CF. Meta-analysis of vitamin D sufficiency for improving survival of patients with breast cancer. Anticancer Res. 2014;34(3):1163-6. 6. Grant WB. 25-Hydroxyvitamin D and breast cancer, colorectal cancer, and colorectal adenomas: case–control versus nested case–control studies, Anticancer Res. 2015 Feb;35(2):in press. 7. 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. 8. Rainville C, Khan Y, Tisman G. Triple negative breast cancer patients presenting with low serum vitamin D levels: a case series. Cases J. 2009;2:8390. 9. Peppone LJ, Rickles AS, Janelsins MC, Insalaco MR, Skinner KA. The association between breast cancer prognostic indicators and serum 25-OH vitamin D levels. Ann Surg Oncol. 2012;19(8):2590-9. 10. Yao S, Ambrosone CB. Associations between vitamin D deficiency and risk of aggressive breast cancer in African-American women. J Steroid Biochem Mol Biol. 2013 Jul;136:337-41. 11. LaPorta E, Welsh J. Modeling vitamin D actions in triple negative/basal-like breast cancer. J Steroid Biochem Mol Biol. 2014;144 Pt A:65-73. 12. Pludowski P, Holick MF, Pilz S, Wagner CL, Hollis BW, Grant WB, Shoenfeld Y, Lerchbaum E, Llewellyn DJ, Kienreich K, Soni M. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality- a review of recent evidence. Autoimmun Rev. 2013;12(10):976-89.

Disclosure I receive funding from Bio-Tech Pharmacal (Fayetteville, AR) and MediSun Technology (Highland Park, IL).

On 2015 Jan 15, William Grant commented:

Differences in 25-hydroxyvitamin D concentrations may explain Much of the black-white-Hispanic differences in breast cancer-specific survival in the United States

In the paper by Iqbal and colleagues, it was found that black women had higher probability of small-sized breast cancer tumors presenting with distant metastases than whites, as well as the highest proportion of triple-negative breast cancers [1]. Black women also had the highest hazard ratio for death for women with stage I breast cancer and tumors less than 2.0 cm in diameter, with Hispanic women having hazard ratios intermediate between those for blacks or whites. The conclusion, "Much of the difference could be statistically accounted for by intrinsic biological differences such as lymph node metastasis, distant metastasis, and triple-negative behavior of tumors." overlooked the fact that there might be explanations for these "intrinsic differences". In this comment, I outline the evidence that differences in 25-hydroxyvitamin D [25(OH)D] concentrations explain much of the findings.

First, there is strong evidence from geographical ecological studies that breast cancer mortality rates are inversely correlated with solar UVB doses [2]. Solar UVB is the primary source of vitamin D for most people. Since those with darker skin make vitamin D less efficiently than those with lighter skin, in the U.S., whites have the highest mean 25(OH)D concentrations, Hispanics intermediate concentrations, and blacks the lowest concentrations [3]. It was noted that these differences seem to explain the black-white cancer-specific and all-cause differences in survival after diagnosis of 13 types of cancer including breast cancer after consideration of socioeconomic status, stage at diagnosis, and treatment [4]. A recent review also found that higher 25(OH)D concentrations were significantly inversely correlated with breast cancer survival [5]. There is also strong evidence from case-control studies that breast cancer incidence is inversely correlated with 25(OH)D concentration [6, 7]. It is pointed out in that paper that nested case-control studies do not find significant inverse correlations because breast cancer tumors develop so rapidly that 25(OHD from blood drawn at the time of enrollment loses relevance as time increases.

Second, some of the findings noted in Ref. 1 are related to 25(OH)D concentrations. Those diagnosed with triple-negative breast cancer have been found to have lower 25(OH)D concentrations [8-10] and the actions of vitamin D on triple-negative breast cancer have been modeled [11].

While more research is required to fully understand the role of UVB and vitamin D in reducing risk of breast cancer and increasing survival after diagnosis, there is enough support for the role of vitamin D related to breast cancer that women who want reduce their risk of developing breast cancer and increase their chance of surviving after diagnosis should be advised to increase their 25(OH)D concentrations to above 75-100 nmol/L, which could take 1000-4000 IU/d vitamin D3 (cholecalciferol) in the absence of adequate UVB exposure [12]. Doing so would also have benefits for many other health outcomes [12].

References 1. Iqbal J, Ginsburg O, Rochon PA, Sun P, Narod SA. Differences in breast cancer stage at diagnosis and cancer-specific survival by race and ethnicity in the United States. JAMA. 2015;313(2):165-173. 2. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5(10):3993-4023. 3. Ginde AA, Liu MC, Camargo CA Jr. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med. 2009;169(6):626-32. 4. 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. 5. Mohr SB, Gorham ED, Kim J, Hofflich H, Garland CF. Meta-analysis of vitamin D sufficiency for improving survival of patients with breast cancer. Anticancer Res. 2014;34(3):1163-6. 6. Grant WB. 25-Hydroxyvitamin D and breast cancer, colorectal cancer, and colorectal adenomas: case–control versus nested case–control studies, Anticancer Res. 2015 Feb;35(2):in press. 7. 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. 8. Rainville C, Khan Y, Tisman G. Triple negative breast cancer patients presenting with low serum vitamin D levels: a case series. Cases J. 2009;2:8390. 9. Peppone LJ, Rickles AS, Janelsins MC, Insalaco MR, Skinner KA. The association between breast cancer prognostic indicators and serum 25-OH vitamin D levels. Ann Surg Oncol. 2012;19(8):2590-9. 10. Yao S, Ambrosone CB. Associations between vitamin D deficiency and risk of aggressive breast cancer in African-American women. J Steroid Biochem Mol Biol. 2013 Jul;136:337-41. 11. LaPorta E, Welsh J. Modeling vitamin D actions in triple negative/basal-like breast cancer. J Steroid Biochem Mol Biol. 2014;144 Pt A:65-73. 12. Pludowski P, Holick MF, Pilz S, Wagner CL, Hollis BW, Grant WB, Shoenfeld Y, Lerchbaum E, Llewellyn DJ, Kienreich K, Soni M. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality- a review of recent evidence. Autoimmun Rev. 2013;12(10):976-89.

Disclosure I receive funding from Bio-Tech Pharmacal (Fayetteville, AR) and MediSun Technology (Highland Park, IL).