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

Kala Visvanathan; Alison M. Mondul; Anne Zeleniuch-Jacquotte; Molin Wang; Mitchell H. Gail; Shiaw Shyuan Yaun; Stephanie J. Weinstein; Marjorie L. McCullough; A. Heather Eliassen; Nancy R. Cook; Claudia Agnoli; Martin Almquist; Amanda Black; Julie E. Buring; Chu Chen; Yu Chen; Tess Clendenen; Laure Dossus; Veronika Fedirko; Gretchen L. Gierach; Edward L. Giovannucci; Gary E. Goodman; Marc T. Goodman; Pascal Guénel; Göran Hallmans; Susan E. Hankinson; Ronald L. Horst; Tao Hou; Wen Yi Huang; Michael E. Jones; Corrine E. Joshu; Rudolf Kaaks; Vittorio Krogh; Tilman Kühn; Marina Kvaskoff; I. Min Lee; Yahya Mahamat-Saleh; Johan Malm; Jonas Manjer; Gertraud Maskarinec; Amy E. Millen; Toqir K. Mukhtar; Marian L. Neuhouser; Trude E. Robsahm; Minouk J. Schoemaker; Sabina Sieri; Malin Sund; Anthony J. Swerdlow; Cynthia A. Thomson; Giske Ursin; Jean Wactawski-Wende; Ying Wang; Lynne R. Wilkens; Yujie Wu; Emilie Zoltick; Walter C. Willett; Stephanie A. Smith-Warner; Regina G. Ziegler

doi:10.1007/s10654-022-00921-1

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

Kala Visvanathan, Alison M. Mondul, Anne Zeleniuch-Jacquotte, Molin Wang, Mitchell H. Gail, Shiaw Shyuan Yaun, Stephanie J. Weinstein, Marjorie L. McCullough, A. Heather Eliassen, Nancy R. Cook, Claudia Agnoli, Martin Almquist, Amanda Black, Julie E. Buring, Chu Chen, Yu Chen, Tess Clendenen, Laure Dossus, Veronika Fedirko, Gretchen L. GierachEdward L. Giovannucci, Gary E. Goodman, Marc T. Goodman, Pascal Guénel, Göran Hallmans, Susan E. Hankinson, Ronald L. Horst, Tao Hou, Wen Yi Huang, Michael E. Jones, Corrine E. Joshu, Rudolf Kaaks, Vittorio Krogh, Tilman Kühn, Marina Kvaskoff, I. Min Lee, Yahya Mahamat-Saleh, Johan Malm, Jonas Manjer, Gertraud Maskarinec, Amy E. Millen, Toqir K. Mukhtar, Marian L. Neuhouser, Trude E. Robsahm, Minouk J. Schoemaker, Sabina Sieri, Malin Sund, Anthony J. Swerdlow, Cynthia A. Thomson, Giske Ursin, Jean Wactawski-Wende, Ying Wang, Lynne R. Wilkens, Yujie Wu, Emilie Zoltick, Walter C. Willett, Stephanie A. Smith-Warner, Regina G. Ziegler

Urban Initiative

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	11-29
Number of pages	19
Journal	European Journal of Epidemiology
Volume	38
Issue number	1
DOIs	https://doi.org/10.1007/s10654-022-00921-1
State	Published - Jan 2023

Keywords

25-Hydroxyvitamin D
Biomarker
Breast cancer
Calibration
Pooled analysis
Prospective cohort study
Vitamin D

ASJC Scopus subject areas

Epidemiology

Access to Document

10.1007/s10654-022-00921-1

Cite this

Visvanathan, K., Mondul, A. M., Zeleniuch-Jacquotte, A., Wang, M., Gail, M. H., Yaun, S. S., Weinstein, S. J., McCullough, M. L., Eliassen, A. H., Cook, N. R., Agnoli, C., Almquist, M., Black, A., Buring, J. E., Chen, C., Chen, Y., Clendenen, T., Dossus, L., Fedirko, V., ... Ziegler, R. G. (2023). Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts. European Journal of Epidemiology, 38(1), 11-29. https://doi.org/10.1007/s10654-022-00921-1

Visvanathan, K, Mondul, AM, Zeleniuch-Jacquotte, A, Wang, M, Gail, MH, Yaun, SS, Weinstein, SJ, McCullough, ML, Eliassen, AH, Cook, NR, Agnoli, C, Almquist, M, Black, A, Buring, JE, Chen, C, Chen, Y, Clendenen, T, Dossus, L, Fedirko, V, Gierach, GL, Giovannucci, EL, Goodman, GE, Goodman, MT, Guénel, P, Hallmans, G, Hankinson, SE, Horst, RL, Hou, T, Huang, WY, Jones, ME, Joshu, CE, Kaaks, R, Krogh, V, Kühn, T, Kvaskoff, M, Lee, IM, Mahamat-Saleh, Y, Malm, J, Manjer, J, Maskarinec, G, Millen, AE, Mukhtar, TK, Neuhouser, ML, Robsahm, TE, Schoemaker, MJ, Sieri, S, Sund, M, Swerdlow, AJ, Thomson, CA, Ursin, G, Wactawski-Wende, J, Wang, Y, Wilkens, LR, Wu, Y, Zoltick, E, Willett, WC, Smith-Warner, SA & Ziegler, RG 2023, 'Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts', European Journal of Epidemiology, vol. 38, no. 1, pp. 11-29. https://doi.org/10.1007/s10654-022-00921-1

@article{37b0917f077a4fde9b673957e0769450,

title = "Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts",

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.",

keywords = "25-Hydroxyvitamin D, Biomarker, Breast cancer, Calibration, Pooled analysis, Prospective cohort study, Vitamin D",

author = "Kala Visvanathan and Mondul, {Alison M.} and Anne Zeleniuch-Jacquotte and Molin Wang and Gail, {Mitchell H.} and Yaun, {Shiaw Shyuan} and Weinstein, {Stephanie J.} and McCullough, {Marjorie L.} and Eliassen, {A. Heather} and Cook, {Nancy R.} and Claudia Agnoli and Martin Almquist and Amanda Black and Buring, {Julie E.} and Chu Chen and Yu Chen and Tess Clendenen and Laure Dossus and Veronika Fedirko and Gierach, {Gretchen L.} and Giovannucci, {Edward L.} and Goodman, {Gary E.} and Goodman, {Marc T.} and Pascal Gu{\'e}nel and G{\"o}ran Hallmans and Hankinson, {Susan E.} and Horst, {Ronald L.} and Tao Hou and Huang, {Wen Yi} and Jones, {Michael E.} and Joshu, {Corrine E.} and Rudolf Kaaks and Vittorio Krogh and Tilman K{\"u}hn and Marina Kvaskoff and Lee, {I. Min} and Yahya Mahamat-Saleh and Johan Malm and Jonas Manjer and Gertraud Maskarinec and Millen, {Amy E.} and Mukhtar, {Toqir K.} and Neuhouser, {Marian L.} and Robsahm, {Trude E.} and Schoemaker, {Minouk J.} and Sabina Sieri and Malin Sund and Swerdlow, {Anthony J.} and Thomson, {Cynthia A.} and Giske Ursin and Jean Wactawski-Wende and Ying Wang and Wilkens, {Lynne R.} and Yujie Wu and Emilie Zoltick and Willett, {Walter C.} and Smith-Warner, {Stephanie A.} and Ziegler, {Regina G.}",

note = "Funding Information: This work was supported by the National Institutes of Health (R01 CA098661, U01 CA182934, P30 CA016087, and P30 ES000260). Funding Information: The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the National Institute for Health Research Imperial Biomedical Research Centre (BRC). The national cohorts are supported by the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G{\'e}n{\'e}rale de l{\textquoteright}Education Nationale, and Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), and Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro (AIRC-Italy), Compagnia di San Paolo, and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland (ZON), World Cancer Research Fund (WCRF), and Statistics Netherlands (The Netherlands); Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andaluc{\'i}a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology—ICO (Spain); Swedish Cancer Society, Swedish Research Council, and County Councils of Sk{\aa}ne and V{\"a}sterbotten (Sweden); and Cancer Research UK (14136 and C8221/A29017) and Medical Research Council (grant numbers 1000143 and MR/M012190/1) (United Kingdom). Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Funding Information: The centralization, checking, harmonization, and statistical analyses of the participant level data from the cohorts; the 25(OH)D assays required for newly measured studies and calibration of previously measured studies; and the laboratory quality control procedures were supported by the National Cancer Institute, National Institutes of Health (R01 CA152071); the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; and the Breast Cancer Research Foundation. Funding Information: This study was supported by the Italian Association for Cancer Research (AIRC). Funding Information: This work was supported by the National Institutes of Health (P01 CA33619 and U01 CA164973). Funding Information: The E3N cohort from the French National Institute of Health and Medical Research (INSERM) was supported by the Mutuelle G{\'e}n{\'e}rale de l{\textquoteright}Education Nationale, the Gustave Roussy Institute, and the French League against Cancer (LNCC). E3N-E4N is also supported by the French National Research Agency (ANR) under the Investment for the Future Program (PIA) (ANR-10-COHO-0006) and by the French Ministry of Higher Education, Research and Innovation (subsidy for public service charges number 2102 918823). Funding Information: This work was supported by the National Institutes of Health (CA047988, CA182913, HL043851, HL080467, and HL099355). Author contributions Funding Information: CLUE II was supported by the National Cancer Institute of the National Institutes of Health (U01 CA86308, P30 CA006973) and the National Institute on Aging of the National Institutes of Health (U01 AG18033). The collection and availability of cancer registry data was also supported by the Centers for Disease Control and Prevention (cooperative agreement NU58DP006333). Cancer data was provided by the Maryland Cancer Registry, Center for Cancer Prevention and Control, Maryland Department of Health, with funding from the State of Maryland and the Maryland Cigarette Restitution Fund. We thank the participants of CLUE II and appreciate the continued efforts of the staff at the Johns Hopkins George W. Comstock Center for Public Health Research and Prevention in the conduct of the CLUE Cohort Studies. The contents of the article are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services. Funding Information: This work was supported by the National Institutes of Health (UM1 CA186107, R01 CA49449, and P01 CA87969). The study protocol was approved by the institutional review boards of the Brigham and Women{\textquoteright}s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. We would like to thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: We thank Breast Cancer Now and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, now called the Generations Study. We acknowledge National Health Service funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. We thank the study participants; study staff; and the doctors, nurses, health care providers, and health information sources who have contributed to the study. Funding Information: This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. We thank the PLCO screening center investigators and the staff from Information Management Services, Inc. and Westat, Inc. Most importantly, we thank the study participants for their contributions that made this study possible. Funding Information: This work was supported by the Swedish Cancer Society, Swedish Research Council, and County Councils of V{\"a}sterbotten (Sweden), and the National Institutes of Health (R01 CA098661). Funding Information: This work was supported by the National Institutes of Health (U01 CA176726, R01 CA67262, R01 CA50385, and P50 CA089393). The study protocol was approved by the institutional review boards of the Brigham and Women{\textquoteright}s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. We would like to thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: This work was supported by the National Institutes of Health (U01 CA063673, UM1 CA167462, and UO1 CA167462). Funding Information: We sincerely thank the Cancer Registry of Norway and the Norwegian Cancer Society for financial funding. Funding Information: The WHI program was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health, U.S. Department of Health and Human Services (HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C). Publisher Copyright: {\textcopyright} 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2023",

month = jan,

doi = "10.1007/s10654-022-00921-1",

language = "English (US)",

volume = "38",

pages = "11--29",

journal = "European Journal of Epidemiology",

issn = "0393-2990",

publisher = "Springer Netherlands",

number = "1",

}

TY - JOUR

T1 - Circulating vitamin D and breast cancer risk

T2 - an international pooling project of 17 cohorts

AU - Visvanathan, Kala

AU - Mondul, Alison M.

AU - Zeleniuch-Jacquotte, Anne

AU - Wang, Molin

AU - Gail, Mitchell H.

AU - Yaun, Shiaw Shyuan

AU - Weinstein, Stephanie J.

AU - McCullough, Marjorie L.

AU - Eliassen, A. Heather

AU - Cook, Nancy R.

AU - Agnoli, Claudia

AU - Almquist, Martin

AU - Black, Amanda

AU - Buring, Julie E.

AU - Chen, Chu

AU - Chen, Yu

AU - Clendenen, Tess

AU - Dossus, Laure

AU - Fedirko, Veronika

AU - Gierach, Gretchen L.

AU - Giovannucci, Edward L.

AU - Goodman, Gary E.

AU - Goodman, Marc T.

AU - Guénel, Pascal

AU - Hallmans, Göran

AU - Hankinson, Susan E.

AU - Horst, Ronald L.

AU - Hou, Tao

AU - Huang, Wen Yi

AU - Jones, Michael E.

AU - Joshu, Corrine E.

AU - Kaaks, Rudolf

AU - Krogh, Vittorio

AU - Kühn, Tilman

AU - Kvaskoff, Marina

AU - Lee, I. Min

AU - Mahamat-Saleh, Yahya

AU - Malm, Johan

AU - Manjer, Jonas

AU - Maskarinec, Gertraud

AU - Millen, Amy E.

AU - Mukhtar, Toqir K.

AU - Neuhouser, Marian L.

AU - Robsahm, Trude E.

AU - Schoemaker, Minouk J.

AU - Sieri, Sabina

AU - Sund, Malin

AU - Swerdlow, Anthony J.

AU - Thomson, Cynthia A.

AU - Ursin, Giske

AU - Wactawski-Wende, Jean

AU - Wang, Ying

AU - Wilkens, Lynne R.

AU - Wu, Yujie

AU - Zoltick, Emilie

AU - Willett, Walter C.

AU - Smith-Warner, Stephanie A.

AU - Ziegler, Regina G.

N1 - Funding Information: This work was supported by the National Institutes of Health (R01 CA098661, U01 CA182934, P30 CA016087, and P30 ES000260). Funding Information: The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the National Institute for Health Research Imperial Biomedical Research Centre (BRC). The national cohorts are supported by the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), and Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro (AIRC-Italy), Compagnia di San Paolo, and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland (ZON), World Cancer Research Fund (WCRF), and Statistics Netherlands (The Netherlands); Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology—ICO (Spain); Swedish Cancer Society, Swedish Research Council, and County Councils of Skåne and Västerbotten (Sweden); and Cancer Research UK (14136 and C8221/A29017) and Medical Research Council (grant numbers 1000143 and MR/M012190/1) (United Kingdom). Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Funding Information: The centralization, checking, harmonization, and statistical analyses of the participant level data from the cohorts; the 25(OH)D assays required for newly measured studies and calibration of previously measured studies; and the laboratory quality control procedures were supported by the National Cancer Institute, National Institutes of Health (R01 CA152071); the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; and the Breast Cancer Research Foundation. Funding Information: This study was supported by the Italian Association for Cancer Research (AIRC). Funding Information: This work was supported by the National Institutes of Health (P01 CA33619 and U01 CA164973). Funding Information: The E3N cohort from the French National Institute of Health and Medical Research (INSERM) was supported by the Mutuelle Générale de l’Education Nationale, the Gustave Roussy Institute, and the French League against Cancer (LNCC). E3N-E4N is also supported by the French National Research Agency (ANR) under the Investment for the Future Program (PIA) (ANR-10-COHO-0006) and by the French Ministry of Higher Education, Research and Innovation (subsidy for public service charges number 2102 918823). Funding Information: This work was supported by the National Institutes of Health (CA047988, CA182913, HL043851, HL080467, and HL099355). Author contributions Funding Information: CLUE II was supported by the National Cancer Institute of the National Institutes of Health (U01 CA86308, P30 CA006973) and the National Institute on Aging of the National Institutes of Health (U01 AG18033). The collection and availability of cancer registry data was also supported by the Centers for Disease Control and Prevention (cooperative agreement NU58DP006333). Cancer data was provided by the Maryland Cancer Registry, Center for Cancer Prevention and Control, Maryland Department of Health, with funding from the State of Maryland and the Maryland Cigarette Restitution Fund. We thank the participants of CLUE II and appreciate the continued efforts of the staff at the Johns Hopkins George W. Comstock Center for Public Health Research and Prevention in the conduct of the CLUE Cohort Studies. The contents of the article are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services. Funding Information: This work was supported by the National Institutes of Health (UM1 CA186107, R01 CA49449, and P01 CA87969). The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. We would like to thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: We thank Breast Cancer Now and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, now called the Generations Study. We acknowledge National Health Service funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. We thank the study participants; study staff; and the doctors, nurses, health care providers, and health information sources who have contributed to the study. Funding Information: This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. We thank the PLCO screening center investigators and the staff from Information Management Services, Inc. and Westat, Inc. Most importantly, we thank the study participants for their contributions that made this study possible. Funding Information: This work was supported by the Swedish Cancer Society, Swedish Research Council, and County Councils of Västerbotten (Sweden), and the National Institutes of Health (R01 CA098661). Funding Information: This work was supported by the National Institutes of Health (U01 CA176726, R01 CA67262, R01 CA50385, and P50 CA089393). The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. We would like to thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: This work was supported by the National Institutes of Health (U01 CA063673, UM1 CA167462, and UO1 CA167462). Funding Information: We sincerely thank the Cancer Registry of Norway and the Norwegian Cancer Society for financial funding. Funding Information: The WHI program was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health, U.S. Department of Health and Human Services (HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C). Publisher Copyright: © 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

PY - 2023/1

Y1 - 2023/1

N2 - 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.

AB - 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.

KW - 25-Hydroxyvitamin D

KW - Biomarker

KW - Breast cancer

KW - Calibration

KW - Pooled analysis

KW - Prospective cohort study

KW - Vitamin D

UR - http://www.scopus.com/inward/record.url?scp=85145419390&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85145419390&partnerID=8YFLogxK

U2 - 10.1007/s10654-022-00921-1

DO - 10.1007/s10654-022-00921-1

M3 - Article

C2 - 36593337

AN - SCOPUS:85145419390

SN - 0393-2990

VL - 38

SP - 11

EP - 29

JO - European Journal of Epidemiology

JF - European Journal of Epidemiology

IS - 1

ER -

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

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