title: Mammographic density and breast cancer risk: a mediation analysis.
abstract: High mammographic density (MD) is a strong risk factor for breast cancer. However, it is unclear whether high MD is an intermediate phenotype or whether breast cancer risk factors influence breast cancer risk and MD independently.
  
  
  
  Our study population included 1290 invasive breast cancer cases and 3422 controls from the Nurses' Health Studies. We estimated the percent of the total association between the risk factor and breast cancer that was mediated by MD.
  
  
  
  In both pre- and postmenopausal women, the association between history of biopsy-confirmed benign breast disease and risk was partially mediated by percent MD (percent mediated (PM) = 17 %, p < 0.01 and PM = 33 %, p = 0.04, respectively). In premenopausal women, the associations between early life body size (adolescent somatotype and BMI at age 18) and breast cancer risk were substantially mediated by percent MD (PM = 73 %, p = 0.05 and PM = 82 %, p = 0.04, respectively). In postmenopausal women, the proportion of the associations of childhood somatotype and adolescent somatotype that were mediated by percent MD were lower (PM = 26 %, p = 0.01 for both measures). Hormone therapy use at mammogram was significantly mediated by percent MD in postmenopausal women (PM = 22 %, p < 0.01). Associations with other risk factors, such as age at menarche or family history of breast cancer, were not mediated by percent MD.
  
  
  
  Percent MD partially mediated some of the associations between risk factors and breast cancer, though the magnitude varied by risk factor and menopausal status. These findings suggest that high MD may be an intermediate in some biological pathways for breast cancer development.
authors.affiliation: Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Bartlett 9, Boston, MA, 02116, USA. mrice1@mgh.harvard.edu.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Rice
authors.affiliation: Slone Epidemiology Center, Boston University, Boston, MA, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Bertrand
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: VanderWeele
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA.
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Rosner
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Liao
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Department of Epidemiology, Institute of Health and Society, University of Oslo, Oslo, Norway.|Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Hans-Olov
authors.initials: HO
authors.lastname: Adami
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Channing Division of Network Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA.
authors.forename: Rulla M
authors.initials: RM
authors.lastname: Tamimi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015992:Body Mass Index; D001940:Breast / Q000000981:diagnostic imaging*; D000071060:Breast Density; D001943:Breast Neoplasms / Q000000981:diagnostic imaging*; D002648:Child; D005260:Female; D006306:Health Surveys / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D008327:Mammography / Q000379:methods / Q000706:statistics & numerical data*; D008875:Middle Aged; D009726:Nurses / Q000706:statistics & numerical data; D017698:Postmenopause; D017697:Premenopause; D018570:Risk Assessment / Q000379:methods / Q000706:statistics & numerical data*; D012307:Risk Factors; D014481:United States