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Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts

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Abstract

Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42–68) years at blood collection and 63 (49–75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50– < 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations (< 20 nmol/L, 3% of controls) or high concentrations (100– < 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95–1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.

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Data availability

The data described in the manuscript will not be made available because we do not have permission to disclose or release the data from the participating cohorts, as specified in their executed data use agreements.

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Author contributions

The Circulating Biomarkers and Breast and Colorectal Cancer Consortium was conceived by WCW, SSW, and RGZ and directed by SSW and RGZ. KV, AMM, AZJ, MW, MHG, SSY, SJW, MLM, AHE, NRC, TH, SSW, and RGZ designed the breast cancer study and developed the methodology. Data were provided by investigators from each participating cohort and harmonized by KV, AMM, AZJ, SSY, TH, TKM, SSW, and RGZ. The vitamin D assays were conducted in the laboratory of RLH. Epidemiologic and statistical analyses were conducted by MW, MHG, SSY, and TH with KV, AMM, AZJ, SSW, and RGZ providing input and interpretation. RGZ wrote the initial draft of the manuscript, with KV, AMM, AZJ, and SSW providing extensive input and review on multiple versions of the manuscript. All authors reviewed, edited, and approved the final version of the manuscript. 

Author information

Author notes

  1. Stephanie A. Smith-Warner and Regina G. Ziegler have contributed equally as senior authors.

  2. Kala Visvanathan, Alison M. Mondul, and Anne Zeleniuch-Jacquotte have contributed equally as first authors.

Authors and Affiliations

  1. Departments of Epidemiology and Oncology, Johns Hopkins Bloomberg School of Public Health and Kimmel Cancer Center, Baltimore, MD, USA

    Kala Visvanathan & Corrine E. Joshu

  2. Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA

    Alison M. Mondul

  3. Departments of Population Health and Environmental Medicine, New York University Grossman School of Medicine, New York, NY, USA

    Anne Zeleniuch-Jacquotte, Yu Chen & Tess Clendenen

  4. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Molin Wang & Yujie Wu

  5. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Molin Wang, A. Heather Eliassen, Nancy R. Cook, Julie E. Buring, Edward L. Giovannucci, I-Min Lee, Walter C. Willett & Stephanie A. Smith-Warner

  6. Channing Division of Network Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA

    Molin Wang, A. Heather Eliassen & Edward L. Giovannucci

  7. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Mitchell H. Gail, Stephanie J. Weinstein, Amanda Black, Gretchen L. Gierach, Wen-Yi Huang & Regina G. Ziegler

  8. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Shiaw-Shyuan Yaun, A. Heather Eliassen, Edward L. Giovannucci, Tao Hou, Walter C. Willett & Stephanie A. Smith-Warner

  9. Department of Population Science, American Cancer Society, Atlanta, GA, USA

    Marjorie L. McCullough & Ying Wang

  10. Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Nancy R. Cook, Julie E. Buring & I-Min Lee

  11. Epidemiology and Prevention Unit, IRCCS National Cancer Institute Foundation, Milan, Italy

    Claudia Agnoli, Vittorio Krogh & Sabina Sieri

  12. Department of Surgery, Skane University Hospital, Lund, Sweden

    Martin Almquist

  13. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Chu Chen, Gary E. Goodman & Marian L. Neuhouser

  14. Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France

    Laure Dossus

  15. Department of Epidemiology, Rollins School of Public Health and Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Veronika Fedirko

  16. Cancer Prevention and Control Research Program, Cedars Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA

    Marc T. Goodman

  17. Center for Research in Epidemiology and Population Health (CESP), French National Institute of Health and Medical Research (INSERM), University Paris-Saclay, Villejuif, France

    Pascal Guénel, Marina Kvaskoff & Yahya Mahamat-Saleh

  18. Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

    Göran Hallmans

  19. Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA, USA

    Susan E. Hankinson

  20. Heartland Assays, LLC, Ames, IA, USA

    Ronald L. Horst

  21. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK

    Michael E. Jones, Minouk J. Schoemaker & Anthony J. Swerdlow

  22. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Rudolf Kaaks & Tilman Kühn

  23. Institute for Global Food Security, Queen’s University, Belfast, Northern Ireland

    Tilman Kühn

  24. Department of Translational Medicine, Lund University, Malmö, Sweden

    Johan Malm

  25. Department of Surgery, Skane University Hospital, Lund University, Malmö, Sweden

    Jonas Manjer

  26. Cancer Epidemiology Program, University of Hawai’i Cancer Center, Honolulu, HI, USA

    Gertraud Maskarinec

  27. Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, USA

    Amy E. Millen & Jean Wactawski-Wende

  28. Department of Primary Care and Public Health, Imperial College, London, UK

    Toqir K. Mukhtar

  29. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    Toqir K. Mukhtar

  30. Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway

    Trude E. Robsahm & Giske Ursin

  31. Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden

    Malin Sund

  32. Division of Breast Cancer Research, The Institute of Cancer Research, London, UK

    Anthony J. Swerdlow

  33. Department of Health Promotion Sciences, Mel and Enid Zuckerman College of Public Health, University of Arizona and University of Arizona Cancer Center, Tucson, AZ, USA

    Cynthia A. Thomson

  34. Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway

    Giske Ursin

  35. Population Sciences in the Pacific, University of Hawai’i Cancer Center, Honolulu, HI, USA

    Lynne R. Wilkens

  36. Department of Population Medicine, Harvard Medical School, Boston, MA, USA

    Emilie Zoltick

Authors
  1. Kala Visvanathan
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  2. Alison M. Mondul
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  3. Anne Zeleniuch-Jacquotte
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  4. Molin Wang
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  5. Mitchell H. Gail
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  6. Shiaw-Shyuan Yaun
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Corresponding author

Correspondence to Regina G. Ziegler.

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No authors have reported conflicts of interest related to the information presented in this manuscript.

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Each participating cohort and the BBC3 coordinating center received approval of this study from its institutional ethics review board.

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The authors agree to publication.

Additional information

Deceased: Ronald L. Horst.

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Visvanathan, K., Mondul, A.M., Zeleniuch-Jacquotte, A. et al. Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts. Eur J Epidemiol 38, 11–29 (2023). https://doi.org/10.1007/s10654-022-00921-1

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  • DOI: https://doi.org/10.1007/s10654-022-00921-1

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