Breast cancer risk markedly lower with serum 25-hydroxyvitamin D concentrations ≥60 vs <20 ng/ml (150 vs 50 nmol/L): Pooled analysis of two randomized trials and a prospective cohort

Background While numerous epidemiologic studies have found an association between higher serum 25-hydroxyvitamin D [25(OH)D] concentrations and lower breast cancer risk, few have assessed this association for concentrations >40 ng/ml. Objective To investigate the relationship between 25(OH)D concentration and breast cancer risk across a broad range of 25(OH)D concentrations among women aged 55 years and older. Methods Analyses used pooled data from two randomized clinical trials (N = 1129, N = 2196) and a prospective cohort (N = 1713) to examine a broad range of 25(OH)D concentrations. The outcome was diagnosis of breast cancer during the observation periods (median: 4.0 years). Three analyses were conducted: 1) Incidence rates were compared according to 25(OH)D concentration from <20 to ≥60 ng/ml (<50 to ≥150 nmol/L), 2) Kaplan-Meier plots were developed and 3) multivariate Cox regression was used to examine the association between 25(OH)D and breast cancer risk using multiple 25(OH)D measurements. Results Within the pooled cohort (N = 5038), 77 women were diagnosed with breast cancer (age-adjusted incidence: 512 cases per 100,000 person-years). Results were similar for the three analyses. First, comparing incidence rates, there was an 82% lower incidence rate of breast cancer for women with 25(OH)D concentrations ≥60 vs <20 ng/ml (Rate Ratio = 0.18, P = 0.006). Second, Kaplan-Meier curves for concentrations of <20, 20–39, 40–59 and ≥60 ng/ml were significantly different (P = 0.02), with the highest proportion breast cancer-free in the ≥60 ng/ml group (99.3%) and the lowest proportion breast cancer-free in the <20 ng/ml group (96.8%). The proportion with breast cancer was 78% lower for ≥60 vs <20 ng/ml (P = 0.02). Third, multivariate Cox regression revealed that women with 25(OH)D concentrations ≥60 ng/ml had an 80% lower risk of breast cancer than women with concentrations <20 ng/ml (HR = 0.20, P = 0.03), adjusting for age, BMI, smoking status, calcium supplement intake, and study of origin. Conclusions Higher 25(OH)D concentrations were associated with a dose-response decrease in breast cancer risk with concentrations ≥60 ng/ml being most protective.

[1]  R. Heaney,et al.  Correction: Serum 25-Hydroxyvitamin D Concentrations ≥40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study , 2018, PloS one.

[2]  J. Vadgama,et al.  Association of Vitamin D3 Level with Breast Cancer Risk and Prognosis in African-American and Hispanic Women , 2017, Cancers.

[3]  Jack A. Taylor,et al.  Serum Vitamin D and Risk of Breast Cancer within Five Years , 2017, Environmental health perspectives.

[4]  K. Baggerly,et al.  Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women: A Randomized Clinical Trial , 2017, JAMA.

[5]  A. Jemal,et al.  Cancer statistics, 2017 , 2017, CA: a cancer journal for clinicians.

[6]  G. Hardiman,et al.  Systems analysis of the prostate transcriptome in African-American men compared with European-American men. , 2016, Pharmacogenomics.

[7]  R. Heaney,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 , 2016, PloS one.

[8]  Wei Li,et al.  Classical and non‐classical metabolic transformation of vitamin D in dermal fibroblasts , 2016, Experimental dermatology.

[9]  Wei Li,et al.  Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland , 2015, Scientific Reports.

[10]  J. Jeon,et al.  Serum 25-hydroxyvitamin D deficiency and increased risk of breast cancer among Korean women: a case–control study , 2015, Breast Cancer Research and Treatment.

[11]  W. Grant.  25-hydroxyvitamin D and breast cancer, colorectal cancer, and colorectal adenomas: case-control versus nested case-control studies. , 2015, Anticancer research.

[12]  J. Welsh,et al.  The impact of vitamin D in breast cancer: genomics, pathways, metabolism , 2014, Front. Physiol..

[13]  J. Chang-Claude,et al.  Plasma 25‐hydroxyvitamin D and the risk of breast cancer in the European prospective investigation into cancer and nutrition: A nested case–control study , 2013, International journal of cancer.

[14]  M. Holick.  Vitamin D, sunlight and cancer connection. , 2012, Anti-cancer agents in medicinal chemistry.

[15]  Jonathan R. Brestoff,et al.  Epidemiology: Principles and Practical Guidelines , 2013 .

[16]  D. Viswanath,et al.  Dietary Reference Intakes for Calcium and Vitamin D , 2012, Pediatrics.

[17]  Wei Li,et al.  In vivo evidence for a novel pathway of vitamin D3 metabolism initiated by P450scc and modified by CYP27B1 , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  E. Garrett-Mayer,et al.  Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance. , 2012, The Journal of clinical endocrinology and metabolism.

[19]  J. Manson,et al.  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. , 2012, American journal of epidemiology.

[20]  K. Skinner,et al.  The Association Between Breast Cancer Prognostic Indicators and Serum 25-OH Vitamin D Levels , 2012, Annals of Surgical Oncology.

[21]  I. Kema,et al.  Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l , 2012, British Journal of Nutrition.

[22]  J. Boyages,et al.  Association between 25-hydroxyvitamin D concentration and breast cancer risk in an Australian population: an observational case–control study , 2012, Breast Cancer Research and Treatment.

[23]  I. Reid,et al.  Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. , 2011, The American journal of clinical nutrition.

[24]  S. Edge,et al.  Pretreatment Serum Concentrations of 25-Hydroxyvitamin D and Breast Cancer Prognostic Characteristics: A Case-Control and a Case-Series Study , 2011, PloS one.

[25]  R. Heaney,et al.  Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. , 2011, Anticancer research.

[26]  Eric J Feuer,et al.  Projections of the cost of cancer care in the United States: 2010-2020. , 2011, Journal of the National Cancer Institute.

[27]  Steve Selvin.  Statistical Tools for Epidemiologic Research , 2011 .

[28]  Christine L. Taylor,et al.  Dietary Reference Intakes for Calcium and Vitamin D , 2016, Pediatric Clinical Practice Guidelines & Policies.

[29]  Thomas J. Wang,et al.  Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. , 2010, Autoimmunity reviews.

[30]  A. Tietze,et al.  Reduced Prediagnostic 25-Hydroxyvitamin D Levels in Women with Breast Cancer: A Nested Case-Control Study , 2009, Cancer Epidemiology, Biomarkers & Prevention.

[31]  M. Thun,et al.  Serum 25-hydroxyvitamin D concentrations and postmenopausal breast cancer risk: a nested case control study in the Cancer Prevention Study-II Nutrition Cohort , 2009, Breast Cancer Research.

[32]  S. Mohr,et al.  Vitamin D for cancer prevention: global perspective. , 2009, Annals of epidemiology.

[33]  A. Neugut,et al.  Association between Plasma 25-Hydroxyvitamin D and Breast Cancer Risk , 2009, Cancer Prevention Research.

[34]  P. Mortensen,et al.  A sensitive LC/MS/MS assay of 25OH vitamin D3 and 25OH vitamin D2 in dried blood spots. , 2009, Clinica chimica acta; international journal of clinical chemistry.

[35]  J. Chang-Claude,et al.  Plasma 25‐hydroxyvitamin D and premenopausal breast cancer risk in a German case‐control study , 2009, International journal of cancer.

[36]  C. McCarty,et al.  Serum Levels of Vitamin D Metabolites and Breast Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial , 2008, Cancer Epidemiology Biomarkers & Prevention.

[37]  M. Zasloff,et al.  Diagnosis and treatment of vitamin D deficiency , 2008, Expert opinion on pharmacotherapy.

[38]  J. Chang-Claude,et al.  Serum 25-hydroxyvitamin D and risk of post-menopausal breast cancer--results of a large case-control study. , 2007, Carcinogenesis.

[39]  R. Recker,et al.  Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. , 2007, The American journal of clinical nutrition.

[40]  E. Giovannucci,et al.  Vitamin D and prevention of breast cancer: Pooled analysis , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[41]  R. Heaney,et al.  Vitamin D Status in a Rural Postmenopausal Female Population , 2006, Journal of the American College of Nutrition.

[42]  W. Willett,et al.  Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. , 2006, The American journal of clinical nutrition.

[43]  M. Feinleib.  National Center for Health Statistics (NCHS) , 2005 .

[44]  M. Guy,et al.  Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population. , 2005, European journal of cancer.

[45]  N. Naing.  Easy way to learn standardization : direct and indirect methods. , 2000, The Malaysian journal of medical sciences : MJMS.

[46]  C. Garland,et al.  Sunlight and breast cancer incidence in the USSR. , 1990, International journal of epidemiology.

[47]  J. F. Young,et al.  Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. , 1990, Preventive medicine.

[48]  C. Garland,et al.  Acid haze air pollution and breast and colon cancer mortality in 20 Canadian cities. , 1989, Canadian journal of public health = Revue canadienne de sante publique.