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Breast tenderness and breast cancer risk in the estrogen plus progestin and estrogen-alone women’s health initiative clinical trials

Breast Cancer Research and Treatment volume 132, pages 275–285 (2012)Cite this article

Abstract

The associations between breast tenderness during use of conjugated equine estrogen (CEE) therapy with or without medroxyprogesterone (MPA) therapy and subsequent breast cancer risk are unknown. We analyzed data from the Women’s Health Initiative Estrogen plus Progestin (N = 16,608, 5.6 years intervention) and estrogen-alone (N = 10,739, 6.8 years intervention) clinical trials until trial close-out (Spring 2005). At baseline and annually, participants underwent mammography and clinical breast exam. Self-reported breast tenderness was assessed at baseline and 12 months. Invasive breast cancer was confirmed by medical record review. The risk of new-onset breast tenderness after 12 months was significantly higher among women assigned to active therapy than placebo (CEE-alone vs. placebo risk ratio [RR] 2.15, 95% confidence interval [CI] 1.97–2.35; CEE + MPA vs. placebo RR 3.07, 95% CI 2.85–3.30). CEE + MPA doubled the risk of invasive breast cancer among women with baseline breast tenderness (hazard ratio [HR] 2.16, 95% CI 1.29–3.74), but had a smaller effect among women without baseline breast tenderness (HR 1.17; 95% CI 0.97–1.41). New-onset breast tenderness was associated with a higher risk of breast cancer among women assigned to CEE + MPA (HR 1.33, 95% CI 1.02–1.72, P = 0.03), but not among women assigned to CEE-alone (HR 0.98, 95% CI 0.62–1.53). New-onset breast tenderness during use of CEE + MPA was associated with increased subsequent breast cancer risk. The association of CEE + MPA therapy with increased breast cancer risk was especially pronounced among women with baseline breast tenderness.

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Acknowledgments

Program office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland). Jacques Rossouw, Shari Ludlam, Joan McGowan, Leslie Ford, and Nancy Geller. Clinical coordinating center: (Fred Hutchinson Cancer Research Center, Seattle, WA). Ross Prentice, Garnet Anderson, Andrea LaCroix, Charles L. Kooperberg; (Medical Research Labs, Highland Heights, KY) Evan Stein; (University of California at San Francisco, San Francisco, CA) Steven Cummings. Clinical centers: (Albert Einstein College of Medicine, Bronx, NY) Sylvia Wassertheil-Smoller; (Baylor College of Medicine, Houston, TX) Haleh Sangi-Haghpeykar; (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (Brown University, Providence, RI) Charles B. Eaton; (Emory University, Atlanta, GA) Lawrence S. Phillips; (Fred Hutchinson Cancer Research Center, Seattle, WA) Shirley Beresford; (George Washington University Medical Center, Washington, DC) Lisa Martin; (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA) Rowan Chlebowski; (Kaiser Permanente Center for Health Research, Portland, OR) Erin LeBlanc; (Kaiser Permanente Division of Research, Oakland, CA) Bette Caan; (Medical College of Wisconsin, Milwaukee, WI) Jane Morley Kotchen; (MedStar Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Northwestern University, Chicago/Evanston, IL) Linda Van Horn; (Rush Medical Center, Chicago, IL) Henry Black; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (State University of New York at Stony Brook, Stony Brook, NY) Dorothy Lane; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Alabama at Birmingham, Birmingham, AL) Cora E. Lewis; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of California at Davis, Sacramento, CA) John Robbins; (University of California at Irvine, CA) F. Allan Hubbell; (University of California at Los Angeles, Los Angeles, CA) Lauren Nathan; (University of California at San Diego, LaJolla/Chula Vista, CA) Robert D. Langer; (University of Cincinnati, Cincinnati, OH) Margery Gass; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Hawaii, Honolulu, HI) J. David Curb; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Massachusetts/Fallon Clinic, Worcester, MA) Judith Ockene; (University of Medicine and Dentistry of New Jersey, Newark, NJ) Norman Lasser; (University of Miami, Miami, FL) Mary Jo O’Sullivan; (University of Minnesota, Minneapolis, MN) Karen Margolis; (University of Nevada, Reno, NV) Robert Brunner; (University of North Carolina, Chapel Hill, NC) Gerardo Heiss; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (University of Tennessee Health Science Center, Memphis, TN) Karen C. Johnson; (University of Texas Health Science Center, San Antonio, TX) Robert Brzyski; (University of Wisconsin, Madison, WI) Gloria E. Sarto; (Wake Forest University School of Medicine, Winston-Salem, NC) Mara Vitolins; (Wayne State University School of Medicine/Hutzel Hospital, Detroit, MI) Michael S. Simon. Women’s health initiative memory study: (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all of the data and had final responsibility for the decision to submit for publication. Dr. Crandall’s work was supported by the Eileen Ogle Award of the Iris Cantor-UCLA Women’s Health Center. The WHI program is funded by National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services contracts N01WH22110, 24152, 32100–2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221.

Conflicts of interest

CC, AA, JC, and JM have no conflicts of interest to declare. AM: consultant or advisory relationships: Novartis, Proctor and Gamble, Merck, Metagenics, Zymogenetic; stock ownership: Merck; honoraria: Wyeth, Novartis; research funding: Wyeth; GA: expert testimony on behalf of Fred Hutchinson Cancer Research Center; RC: consultant or advisory relationships: Novartis, Pfizer, Astra Zeneca; Honoraria: Novartis, Astra Zeneca; Research funding: Amgen.

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Affiliations

  1. Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles UCLA Medicine/GIM, 911 Broxton Avenue, 1st Floor, Los Angeles, CA, 90024, USA

    Carolyn J. Crandall

  2. WHI Clinical Coordinating Center, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA, 98109, USA

    Aaron K. Aragaki

  3. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Crabtree Hall A547 130 DeSoto Street, Pittsburgh, PA, 15213, USA

    Jane A. Cauley

  4. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M4-B874, P.O. Box 19024, Seattle, WA, 98109-1024, USA

    Anne McTiernan

  5. Department of Epidemiology, Brigham & Women’s Hospital, Harvard Medical School, 3rd Floor, 900 Commonwealth Avenue, Boston, MA, 02215, USA

    JoAnn E. Manson

  6. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Box MP-1002, 1100 Fairview Avenue North, Seattle, WA, 98109, USA

    Garnet Anderson

  7. Department of Hematology and Oncology, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Los Angeles, 90095-1768, CA, USA

    Rowan T. Chlebowski

  8. Department of Hematology and Oncology, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1000 W Carson Street, Box 453, P.O. Box 951768, Torrance, CA, 90509, USA

    Rowan T. Chlebowski

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  1. Carolyn J. Crandall
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  2. Aaron K. Aragaki
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  5. JoAnn E. Manson
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Correspondence to Carolyn J. Crandall.

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Crandall, C.J., Aragaki, A.K., Cauley, J.A. et al. Breast tenderness and breast cancer risk in the estrogen plus progestin and estrogen-alone women’s health initiative clinical trials. Breast Cancer Res Treat 132, 275–285 (2012). https://doi.org/10.1007/s10549-011-1848-9

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Keywords

  • Breast tenderness
  • Breast cancer
  • Menopausal hormone therapy
  • Conjugated equine estrogens
  • Medroxyprogesterone acetate