Abstract
Menstrual and reproductive history and postmenopausal hormone use are well-established risk factors for breast cancer. However, previous studies that have assessed these factors in association with risk of benign proliferative epithelial disorders (BPED) of the breast, putative precursors of breast cancer, have yielded inconsistent findings. To investigate these associations, we conducted a cohort study among 68,132 postmenopausal women enrolled in the Women’s Health Initiative randomized clinical trials. Women were prospectively followed and those reporting an open surgical biopsy or a core needle biopsy had histological sections obtained for centralized pathology review. Over an average of 7.8 years of follow-up, we identified 1,792 women with BPED of the breast. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence limits (CLs) for the associations of interest. Menstrual and reproductive histories were not associated with risk of BPED of the breast, overall or by histological subtype. Women who had used postmenopausal hormones for 15 years or more had a two-fold increase in risk of BPED of the breast compared to women who had never used postmenopausal hormones (HR = 2.03 95% CL = 1.73, 2.38) and the increase in risk was observed for both BPED of the breast without atypia and for atypical hyperplasia. Furthermore, the risk of BPED of the breast decreased with time since cessation of use so that there was essentially no increase in risk 5 or more years after ending use (HR for stopping ≥5 years earlier = 0.96, 95%CL = 0.79, 1.16; HR for stopping <5 years earlier = 1.32, 95% CL = 1.08,1.61).
Similar content being viewed by others
References
Rohan TE, Kandel RA (2002) Breast. In: Franco EL, Rohan TE (eds) Cancer precursors: epidemiology, detection, and prevention. Springer-Verlag, New York
Fitzgibbons PL, Henson DE, Hutter RV (1998) Benign breast changes and the risk for subsequent breast cancer: an update of the 1985 consensus statement. Cancer Committee of the College of American Pathologists. Arch Pathol Lab Med 122:1053–1055
Lakhani SR (1999) The transition from hyperplasia to invasive carcinoma of the breast. J Pathol 187:272–278
Henderson BE, Feigelson HS (2000) Hormonal carcinogenesis. Carcinogenesis 21:427–433
Berkowitz GS, Kelsey JL, LiVolsi VA et al (1984) Exogenous hormone use and fibrocystic breast disease by histopathologic component. Int J Cancer 34:443–449
Berkowitz GS, Kelsey JL, LiVolsi VA et al (1985) Risk factors for fibrocystic breast disease and its histopathologic components. J Natl Cancer Inst 75:43–50
Bright RA, Morrison AS, Brisson J et al (1989) Histologic and mammographic specificity of risk factors for benign breast disease. Cancer 64:653–657
Friedenreich C, Bryant H, Alexander F et al (2000) Risk factors for benign proliferative breast disease. Int J Epidemiol 29:637–644
Hsieh CC, Walker AM, Trapido EJ et al (1984) Age at first birth and breast atypia. Int J Cancer 33:309–312
LiVolsi VA, Stadel BV, Kelsey JL et al (1978) Fibrocystic breast disease in oral-contraceptive users. A histopathological evaluation of epithelial atypia. N Engl J Med 299:381–385
Minami Y, Ohuchi N, Taeda Y et al (1998) Risk factors for benign breast disease according to histopathological type: comparisons with risk factors for breast cancer. Jpn J Cancer Res 89:116–123
Pastides H, Kelsey JL, LiVolsi VA et al (1983) Oral contraceptive use and fibrocystic breast disease with special reference to its histopathology. J Natl Cancer Inst 71:5–9
Rohan TE, L’Abbe KA, Cook MG (1992) Oral contraceptives and risk of benign proliferative epithelial disorders of the breast. Int J Cancer 50:891–894
Rohan TE, Miller AB (1999) A cohort study of oral contraceptive use and risk of benign breast disease. Int J Cancer 82:191–196
Rohan TE, Miller AB (1999) Hormone replacement therapy and risk of benign proliferative epithelial disorders of the breast. Eur J Cancer Prev 8:123–130
Soini I, Aine R, Lauslahti K et al (1981) Independent risk factors of benign and malignant breast lesions. Am J Epidemiol 114:507–514
The Women’s Health Initiative Study Group (1998) Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 19:61–109
Jackson RD, LaCroix AZ, Cauley JA et al (2003) The women’s health initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Ann Epidemiol 13:S98–S106
Ritenbaugh C, Patterson RE, Chlebowski RT et al (2003) The Women’s Health Initiative Dietary Modification trial: overview and baseline characteristics of participants. Ann Epidemiol 13:S87–S97
Stefanick ML, Cochrane BB, Hsia J et al (2003) The Women’s Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Ann Epidemiol 13:S78–S86
Hartmann LC, Sellers TA, Frost MH et al (2005) Benign breast disease and the risk of breast cancer. N Engl J Med 353:229–237
Cui Y, Page DL, Chlebowski RT et al (2007) Cigarette smoking and risk of benign proliferative epithelial disorders of the breast in the Women’s Health Initiative. Cancer Causes Control 18:431–438
Cui Y, Page DL, Chlebowski RT et al (2007) Alcohol and folate consumption and risk of benign proliferative epithelial disorders of the breast. Int J Cancer 121:1346–1351
Rothman JK, Greenland S (eds) (1998) Modern epidemiology. Lippincott-Raven, Philadelphia (PA)
Key T, Appleby P, Barnes I et al (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94:606–616
Collaborative Group on Hormonal Factors in Breast Cancer (1997) Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350:1047–1059
Rossouw JE, Anderson GL, Prentice RL et al (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333
Schairer C, Hill D, Sturgeon SR et al (2005) Serum concentrations of estrogens, sex hormone binding globulin, and androgens and risk of breast hyperplasia in postmenopausal women. Cancer Epidemiol Biomarkers Prev 14:1660–1665
Jacquemier JD, Rolland PH, Vague D et al (1982) Relationships between steroid receptor and epithelial cell proliferation in benign fibrocystic disease of the breast. Cancer 49:2534–2536
Giani C, D’Amore E, Delarue JC et al (1986) Estrogen and progesterone receptors in benign breast tumors and lesions: relationship with histological and cytological features. Int J Cancer 37:7–10
Tan-Chiu E, Wang J, Costantino JP et al (2003) Effects of tamoxifen on benign breast disease in women at high risk for breast cancer. J Natl Cancer Inst 95:302–307
Anderson GL, Limacher M, Assaf AR et al (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291:1701–1712
Cline JM, Soderqvist G, von Schoultz E et al (1996) Effects of hormone replacement therapy on the mammary gland of surgically postmenopausal cynomolgus macaques. Am J Obstet Gynecol 174:93–100
Cook MG, Rohan TE (1985) The patho-epidemiology of benign proliferative epithelial disorders of the female breast. J Pathol 146:1–15
Acknowledgments
The study is supported by NIH grant RO1-CA77290.We are indebted to the participants and investigators in the Women’s Health Initiative Clinical Trial. We also thank Mindy Ginsberg and Mary Pettinger for managing the datasets.
Author information
Authors and Affiliations
Corresponding author
Appendix
Appendix
List of participating WHI investigators: Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Barbara Alving, Jacques Rossouw, Shari Ludlam, Linda Pottern, 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, Ruth E. Patterson, Anne McTiernan; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker; (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) Jennifer Hays; (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA) JoAnn Manson; (Brown University, Providence, RI) Annlouise R. Assaf; (Emory University, Atlanta, GA) Lawrence Phillips; (Fred Hutchinson Cancer Research Center, Seattle, WA) Shirley Beresford; (George Washington University Medical Center, Washington, DC) Judith Hsia; (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA) Rowan Chlebowski; (Kaiser Permanente Center for Health Research, Portland, OR) Evelyn Whitlock; (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) Tamsen Bassford; (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) Howard Judd; (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) 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, 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) Denise Bonds; (Wayne State University School of Medicine/Hutzel Hospital, Detroit, MI) Susan Hendrix.
Rights and permissions
About this article
Cite this article
Cui, Y., Page, D.L., Lane, D.S. et al. Menstrual and reproductive history, postmenopausal hormone use, and risk of benign proliferative epithelial disorders of the breast: a cohort study. Breast Cancer Res Treat 114, 113–120 (2009). https://doi.org/10.1007/s10549-008-9973-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-008-9973-9