Journal of the National Cancer Institute Advance Access published online on November 11, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn360
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© The Author 2008. Published by Oxford University Press.
ARTICLES |
Calcium Plus Vitamin D Supplementation and the Risk of Breast Cancer
Affiliations of authors: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA (RTC); Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN (KCJ); Fred Hutchinson Cancer Research Center, Seattle, WA (CK, MP); Department of Social and Preventive Medicine, State University of New York, Buffalo, NY (JW-W); Albert Einstein College of Medicine, Bronx, NY (TR); National Heart, Lung, and Blood Institute, Bethesda, MD (JR); Department of Preventive Medicine, State University of New York, Stony Brook, NY (DL); Department of Obstetrics-Gynecology, University of Miami, Miami, FL (MJO); Department of Medicine, University of California at Davis, Sacramento, CA (SY); Department of Epidemiology & Biostatics, University of California at San Francisco, San Francisco, CA (RAH); Department of Preventive Medicine, University of Alabama, Birmingham, AL (JMS); Department of Public Health Sciences, Wake Forest University, Winston-Salem, NC (MV); Department of Medicine, Northwestern University, Chicago/Evanston, IL (JK); Department of Medicine, University of California, Irvine, CA (FAH)
Correspondence to: Rowan T. Chlebowski, MD, PhD, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA 90502 (e-mail: rchlebowski{at}gmail.com).
Background: Although some observational studies have associated higher calcium intake and especially higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk, no randomized trial has evaluated these relationships.
Methods: Postmenopausal women (N = 36 282) who were enrolled in a Women's Health Initiative clinical trial were randomly assigned to 1000 mg of elemental calcium with 400 IU of vitamin D3 daily or placebo for a mean of 7.0 years to determine the effects of supplement use on incidence of hip fracture. Mammograms and breast exams were serially conducted. Invasive breast cancer was a secondary outcome. Baseline serum 25-hydroxyvitamin D levels were assessed in a nested case–control study of 1067 case patients and 1067 control subjects. A Cox proportional hazards model was used to estimate the risk of breast cancer associated with random assignment to calcium with vitamin D3. Associations between 25-hydroxyvitamin D serum levels and total vitamin D intake, body mass index (BMI), recreational physical activity, and breast cancer risks were evaluated using logistic regression models. Statistical tests were two-sided.
Results: Invasive breast cancer incidence was similar in the two groups (528 supplement vs 546 placebo; hazard ratio = 0.96; 95% confidence interval = 0.85 to 1.09). In the nested case–control study, no effect of supplement group assignment on breast cancer risk was seen. Baseline 25-hydroxyvitamin D levels were modestly correlated with total vitamin D intake (diet and supplements) (r = 0.19, P < .001) and were higher among women with lower BMI and higher recreational physical activity (both P < .001). Baseline 25-hydroxyvitamin D levels were not associated with breast cancer risk in analyses that were adjusted for BMI and physical activity (Ptrend = .20).
Conclusions: Calcium and vitamin D supplementation did not reduce invasive breast cancer incidence in postmenopausal women. In addition, 25-hydroxyvitamin D levels were not associated with subsequent breast cancer risk. These findings do not support a relationship between total vitamin D intake and 25-hydroxyvitamin D levels with breast cancer risk.
| CONTEXT AND CAVEATS Prior knowledge Some observational studies have reported associations of higher calcium intake and especially higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk, but these relationships have not been analyzed in randomized trials. Study design Randomized double-blind placebo-controlled clinical trial of calcium and vitamin D supplementation vs placebo among postmenopausal women and a nested case–control study of associations between baseline serum 25-hydroxyvitamin D levels, breast cancer risk factors, and risk of breast cancer. Contribution Incidence of invasive breast cancer was similar in the two randomized groups after a mean of 7 years. Baseline serum 25-hydroxyvitamin D levels were correlated with supplement use and were higher among women who did more recreational physical activity and had a lower body mass index (BMI), but they were not associated with breast cancer risk after adjustment for BMI and physical activity. Implications Vitamin D and calcium supplementation has no detectable effect on the risk of postmenopausal invasive breast cancer. Limitations Additional use of calcium and vitamin D supplements was allowed during the study. The duration of calcium and vitamin D supplementation was short compared with how long it takes to develop breast cancer. From the Editors
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The funding organization had representation on the steering committee, which governed the design and conduct of the study, the interpretation of the data, and the preparation and approval of manuscripts. The National Heart, Lung and Blood Institute Program Office reviewed the manuscript prior to publication. Dr Chlebowski is a consultant for AstraZeneca, Novartis, and Eli Lilly and has received grant support from Eli Lilly. No other authors have disclosures to report. We acknowledge the dedicated efforts of the study participants and that of participant staff.
Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Elizabeth Nabel, Jacques Rossouw, Shari Ludlam, Joan McGowan, Nancy Geller, and Leslie Ford.
Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Ross Prentice, Garnet Anderson, Andrea LaCroix, Ruth Patterson, Anne McTiernan, Barbara Cochrane, Julie Hunt, Lesley Tinker, Charles Kooperberg, Martin McIntosh, C. Y. Wang, Chu Chen, Deborah Bowen, Alan Kristal, Janet Stanford, Nicole Urban, Noel Weiss, and Emily White; (Medical Research Laboratories, Highland Heights, KY) Evan Stein and Peter Laskarzewski; (San Francisco Coordinating Center, San Francisco, CA) Steven R. Cummings and Michael Nevitt, Lisa Palermo; (University of Minnesota, Minneapolis, MN) Lisa Harnack; (Fisher BioServices, Rockville, MD) Frank Cammarata and Steve Lindenfelser; (University of Washington, Seattle, WA) Bruce Psaty and Susan Heckbert.
Clinical Centers: (Albert Einstein College of Medicine, Bronx, NY) Sylvia Wassertheil-Smoller, William Frishman, Judith Wylie-Rosett, David Barad, and Ruth Freeman; (Baylor College of Medicine, Houston, TX) Aleksandar Rajkovic, Jennifer Hays, Ronald Young, and Haleh Sangi-Haghpeykar; (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson, Kathryn M. Rexrode, Brian Walsh, J. Michael Gaziano, and Maria Bueche; (Brown University, Providence, RI) Charles B. Eaton, Michele Cyr, and Gretchen Sloane; (Emory University, Atlanta, GA) Lawrence Phillips, Vicki Butler, and Vivian Porter; (Fred Hutchinson Cancer Research Center, Seattle, WA) Shirley A. A. Beresford, Vicky M. Taylor, Nancy F. Woods, Maureen Henderson, and Robyn Andersen; (George Washington University, Washington, DC) Lisa Martin, Judith Hsia, Nancy Gaba, and Richard Katz; (Harbor-UCLA Research and Education Institute, Torrance, CA) Rowan Chlebowski, Robert Detrano, Anita Nelson, and Michele Geller; (Kaiser Permanente Center for Health Research, Portland, OR) Yvonne Michael, Evelyn Whitlock, Victor Stevens, and Njeri Karanja; (Kaiser Permanente Division of Research, Oakland, CA) Bette Caan, Stephen Sidney, and Geri Bailey Jane Hirata; (Medical College of Wisconsin, Milwaukee, WI) Jane Morley Kotchen, Vanessa Barnabei, Theodore A. Kotchen, Mary Ann C. Gilligan, and Joan Neuner; (MedStar Research Institute/Howard University, Washington, DC) Barbara V. Howard, Lucile Adams-Campbell, Lawrence Lessin, Cheryl Iglesia, and Linda K. Mickel; (Northwestern University, Chicago/Evanston, IL) Linda Van Horn, Philip Greenland, Janardan Khandekar, Kiang Liu, and Carol Rosenberg; (Rush University Medical Center, Chicago, IL) Henry Black, Lynda Powell, Ellen Mason, and Martha Gulati; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick, Mark A. Hlatky, Bertha Chen, Randall S. Stafford, and Sally Mackey; (State University of New York at Stony Brook, Stony Brook, NY) Dorothy Lane, Iris Granek, William Lawson, Catherine Messina, and Gabriel San Roman; (The Ohio State University, Columbus, OH) Rebecca Jackson, Randall Harris, Electra Paskett, W. Jerry Mysiw, and Michael Blumenfeld; (University of Alabama at Birmingham, Birmingham, AL) Cora E. Lewis, Albert Oberman, James M. Shikany, and Monika Safford; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A Thomson, Tamsen Bassford, Cheryl Ritenbaugh, Zhao Chen, and Marcia Ko; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende, Maurizio Trevisan, Ellen Smit, Susan Graham, and June Chang; (University of California at Davis, Sacramento, CA) John Robbins and S. Yasmeen; (University of California at Irvine, Irvine, CA) F. Allan Hubbell, Gail Frank, Nathan Wong, Nancy Greep, and Bradley Monk; (University of California at Los Angeles, Los Angeles, CA) Lauren Nathan, David Heber, Robert Elashoff, and Simin Liu; (University of California at San Diego, LaJolla/Chula Vista, CA) Robert D. Langer, Michael H. Criqui, Gregory T. Talavera, Cedric F. Garland, and Matthew A. Allison; (University of Cincinnati, Cincinnati, OH) Margery Gass and Nelson Watts; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher, Michael Perri, Andrew Kaunitz, R. Stan Williams, and Yvonne Brinson; (University of Hawaii, Honolulu, HI) J. David Curb, Helen Petrovitch, Beatriz Rodriguez, Kamal Masaki, and Patricia Blanchette; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace, James Torner, Susan Johnson, Linda Snetselaar, and Jennifer Robinson; (University of Massachusetts/Fallon Clinic, Worcester, MA) Judith Ockene, Milagros Rosal, Ira Ockene, Robert Yood, and Patricia Aronson; (University of Medicine and Dentistry of New Jersey, Newark, NJ) Norman Lasser, Baljinder Singh, Vera Lasser, John Kostis, and Peter McGovern; (University of Miami, Miami, FL) Mary Jo O’Sullivan, Linda Parker, JoNell Potter, Diann Fernandez, and Pat Caralis; (University of Minnesota, Minneapolis, MN) Karen L. Margolis, Richard H. Grimm, Mary F. Perron, Cynthia Bjerk, and Sarah Kempainen; (University of Nevada, Reno, NV) Robert Brunner, William Graettinger, Vicki Oujevolk, and Michael Bloch; (University of North Carolina, Chapel Hill, NC) Gerardo Heiss, Pamela Haines, David Ontjes, Carla Sueta, and Ellen Wells; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller, Jane Cauley, and N. Carole Milas; (University of Tennessee Health Science Center, Memphis, TN) Karen C. Johnson, Suzanne Satterfield, Rongling Li, Stephanie Connelly, and Fran Tylavsky; (University of Texas Health Science Center, San Antonio, TX) Robert Brzyski and Robert Schenken; (University of Wisconsin, Madison, WI) Gloria E. Sarto, Douglas Laube, Patrick McBride, Julie Mares, and Barbara Loevinger; (Wake Forest University School of Medicine, Winston-Salem, NC) Mara Vitolins, Greg Burke, Robin Crouse, and Scott Washburn; (Wayne State University School of Medicine/Hutzel Hospital, Detroit, MI) Michael Simon.
Women's Health Initiative Memory Study: (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker, Stephen Rapp, Claudine Legault, Mark Espeland, and Laura Coker.
Former Principal Investigators and Project Officers: (Baylor College of Medicine, Houston, TX) Jennifer Hays and John Foreyt; (Brown University, Providence, RI) Annlouise R. Assaf; (Emory University, Atlanta, GA) Dallas Hall; (George Washington University, Washington, DC) Valery Miller; (Kaiser Permanente Center for Health Research, Portland, OR) Barbara Valanis; (Kaiser Permanente Division of Research, Oakland, CA) Robert Hiatt; (National Cancer Institute, Bethesda, MD) Carolyn Clifford (deceased); (National Heart, Lung, and Blood Institute, Bethesda, MD) Linda Pottern; (University of California at Irvine, Irvine, CA) Frank Meyskens Jr; (University of California at Los Angeles, Los Angeles, CA) Howard Judd (deceased); (University of Cincinnati, Cincinnati, OH) James Liu and Nelson Watts; (University of Miami, Miami, FL) Marianna Baum; (University of Minnesota, Minneapolis, MN) Richard Grimm; (University of Nevada, Reno, NV) Sandra Daugherty (deceased); (University of North Carolina, Chapel Hill, NC) David Sheps and Barbara Hulka; (University of Tennessee Health Science Center, Memphis, TN) William Applegate; (University of Wisconsin, Madison, WI) Catherine Allen (deceased); (Wake Forest University School of Medicine, Winston-Salem, NC) Denise Bonds.
Manuscript received April 28, 2008; revised August 29, 2008; accepted September 4, 2008.
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J Natl Cancer Inst 2008 100: 1561.
J Natl Cancer Inst 2008 100: 1561.
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