Breast Cancer Research and Treatment

, Volume 170, Issue 1, pp 129–141 | Cite as

Does mammographic density mediate risk factor associations with breast cancer? An analysis by tumor characteristics

  • Megan S. RiceEmail author
  • Rulla M. Tamimi
  • Kimberly A. Bertrand
  • Christopher G. Scott
  • Matthew R. Jensen
  • Aaron D. Norman
  • Daniel W. Visscher
  • Yunn-Yi Chen
  • Kathleen R. Brandt
  • Fergus J. Couch
  • John A. Shepherd
  • Bo Fan
  • Fang-Fang Wu
  • Lin Ma
  • Laura C. Collins
  • Steven R. Cummings
  • Karla Kerlikowske
  • Celine M. Vachon



Though mammographic density (MD) has been proposed as an intermediate marker of breast cancer risk, few studies have examined whether the associations between breast cancer risk factors and risk are mediated by MD, particularly by tumor characteristics.


Our study population included 3392 cases (1105 premenopausal) and 8882 (3192 premenopausal) controls from four case–control studies. For established risk factors, we estimated the percent of the total risk factor association with breast cancer that was mediated by percent MD (secondarily, by dense area and non-dense area) for invasive breast cancer as well as for subtypes defined by the estrogen receptor (ER+/ER−), progesterone receptor (PR+/PR−), and HER2 (HER2+/HER2−). Analyses were conducted separately in pre- and postmenopausal women.


Positive associations between prior breast biopsy and risk of invasive breast cancer as well as all subtypes were partially mediated by percent MD in pre- and postmenopausal women (percent mediated = 11–27%, p ≤ 0.02). In postmenopausal women, nulliparity and hormone therapy use were positively associated with invasive, ER+ , PR+ , and HER2− breast cancer; percent MD partially mediated these associations (percent mediated ≥ 31%, p ≤ 0.02). Further, among postmenopausal women, percent MD partially mediated the positive association between later age at first birth and invasive as well as ER+ breast cancer (percent mediated = 16%, p ≤ 0.05).


Percent MD partially mediated the associations between breast biopsy, nulliparity, age at first birth, and hormone therapy with risk of breast cancer, particularly among postmenopausal women, suggesting that these risk factors at least partially influence breast cancer risk through changes in breast tissue composition.


Mammographic density Breast cancer 



We would like to thank the participants and staff of the Nurses’ Health Study, Nurses’ Health Study II, Mayo Mammography Health Study, the San Francisco Bay Area Breast Cancer SPORE, and the San Francisco Mammography Registry for their valuable contributions as well as 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 authors assume full responsibility for analyses and interpretation of these data.


This work was supported in part by the following NIH, NCI grants: R01 CA140286, R01 CA128931, and R01 CA97396 (to C.M. Vachon); R01 CA124865 and R01 CA131332 (to R.M. Tamimi); P50 CA116201 to Dr. Ingle (F.J. Couch has Project on SPORE); P50 CA58207, U01 CA63740, and P01 CA154292 (to K. Kerlikowske); P01CA087969 and UM1 CA186107 to Dr. Stampfer (supporting NHS); and R01 CA050385, UM1 CA176726, and Breast Cancer Research Foundation to Dr. Willett (supporting NHS2). Additional support was provided by the Simeon J. Fortin Charitable Foundation, Bank of America, N.A., Co-Trustee to Dr. Bertrand; Department of Defense (DAMD 17-00-1-033; to C.M. Vachon).

Compliance with ethical standards

Conflicts of Interest

The Authors declare that they have no conflict of interest.

Supplementary material

10549_2018_4735_MOESM1_ESM.docx (108 kb)
Supplementary material 1 (DOCX 107 kb)


  1. 1.
    McCormack VA, dos Santos Silva I (2006) Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomark Prev 15(6):1159–1169CrossRefGoogle Scholar
  2. 2.
    Boyd NF, Martin LJ, Yaffe MJ, Minkin S (2011) Mammographic density and breast cancer risk: current understanding and future prospects. Breast Cancer Res 13(6):223CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Harris HR, Tamimi RM, Willett WC, Hankinson SE, Michels KB (2011) Body size across the life course, mammographic density, and risk of breast cancer. Am J Epidemiol 174(8):909–918CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Boyd NF, Martin LJ, Li Q, Sun L, Chiarelli AM, Hislop G, Yaffe MJ, Minkin S (2006) Mammographic density as a surrogate marker for the effects of hormone therapy on risk of breast cancer. Cancer Epidemiol Biomark Prev 15(5):961–966CrossRefGoogle Scholar
  5. 5.
    Rice MS, Bertrand KA, VanderWeele TJ, Rosner BA, Liao X, Adami HO, Tamimi RM (2016) Mammographic density and breast cancer risk: a mediation analysis. Breast Cancer Res 18(1):94CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Byrne C, Ursin G, Martin CF, Peck JD, Cole EB, Zeng D, Kim E, Yaffe MD, Boyd NF, Heiss G et al (2017) Mammographic density change with estrogen and progestin therapy and breast cancer risk. J Natl Cancer Inst 109(9):001CrossRefGoogle Scholar
  7. 7.
    Bertrand KA, Tamimi RM, Scott CG, Jensen MR, Pankratz V, Visscher D, Norman A, Couch F, Shepherd J, Fan B et al (2013) Mammographic density and risk of breast cancer by age and tumor characteristics. Breast Cancer Res 15(6):R104CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bertrand KA, Scott CG, Tamimi RM, Jensen MR, Pankratz VS, Norman AD, Visscher DW, Couch FJ, Shepherd J, Chen YY et al (2015) Dense and nondense mammographic area and risk of breast cancer by age and tumor characteristics. Cancer Epidemiol Biomark Prev 24(5):798–809CrossRefGoogle Scholar
  9. 9.
    Tamimi RM, Baer HJ, Marotti J, Galan M, Galaburda L, Fu Y, Deitz AC, Connolly JL, Schnitt SJ, Colditz GA et al (2008) Comparison of molecular phenotypes of ductal carcinoma in situ and invasive breast cancer. Breast Cancer Res 10(4):R67CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Boyd NF, Stone J, Martin LJ, Jong R, Fishell E, Yaffe M, Hammond G, Minkin S (2002) The association of breast mitogens with mammographic densities. Br J Cancer 87(8):876–882CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Shepherd JA, Kerlikowske K, Ma L, Duewer F, Fan B, Wang J, Malkov S, Vittinghoff E, Cummings SR (2011) Volume of mammographic density and risk of breast cancer. Cancer Epidemiol Biomark Prev 20(7):1473–1482CrossRefGoogle Scholar
  12. 12.
    Nevo D, Liao X, Spiegelman D (2017) Estimation and inference for the mediation proportion. Int J Biostat. PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Pettersson A, Hankinson SE, Willett WC, Lagiou P, Trichopoulos D, Tamimi RM (2011) Nondense mammographic area and risk of breast cancer. Breast Cancer Res 13(5):R100CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Nelson HD, O’Meara ES, Kerlikowske K, Balch S, Miglioretti D (2016) Factors associated with rates of false-positive and false-negative results from digital mammography screening: an analysis of registry data. Ann Intern Med 164(4):226–235CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Cuzick J, Warwick J, Pinney E, Duffy SW, Cawthorn S, Howell A, Forbes JF, Warren RM (2011) Tamoxifen-induced reduction in mammographic density and breast cancer risk reduction: a nested case-control study. J Natl Cancer Inst 103(9):744–752CrossRefPubMedGoogle Scholar
  16. 16.
    Cuzick J, Warwick J, Pinney E, Warren RM, Duffy SW (2004) Tamoxifen and breast density in women at increased risk of breast cancer. J Natl Cancer Inst 96(8):621–628CrossRefPubMedGoogle Scholar
  17. 17.
    McTiernan A, Martin CF, Peck JD, Aragaki AK, Chlebowski RT, Pisano ED, Wang CY, Brunner RL, Johnson KC, Manson JE et al (2005) Estrogen-plus-progestin use and mammographic density in postmenopausal women: women’s health initiative randomized trial. J Natl Cancer Inst 97(18):1366–1376CrossRefPubMedGoogle Scholar
  18. 18.
    Boyd NF, Dite GS, Stone J, Gunasekara A, English DR, McCredie MR, Giles GG, Tritchler D, Chiarelli A, Yaffe MJ et al (2002) Heritability of mammographic density, a risk factor for breast cancer. N Engl J Med 347(12):886–894CrossRefPubMedGoogle Scholar
  19. 19.
    Mucci LA, Hjelmborg JB, Harris JR, Czene K, Havelick DJ, Scheike T, Graff RE, Holst K, Moller S, Unger RH et al (2016) Familial risk and heritability of cancer among twins in Nordic countries. JAMA 315(1):68–76CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Moller S, Mucci LA, Harris JR, Scheike T, Holst K, Halekoh U, Adami HO, Czene K, Christensen K, Holm NV et al (2016) The heritability of breast cancer among women in the Nordic twin study of cancer. Cancer Epidemiol Biomark Prev 25(1):145–150CrossRefGoogle Scholar
  21. 21.
    Gierach GL, Loud JT, Chow CK, Prindiville SA, Eng-Wong J, Soballe PW, Giambartolomei C, Mai PL, Galbo CE, Nichols K et al (2010) Mammographic density does not differ between unaffected BRCA1/2 mutation carriers and women at low-to-average risk of breast cancer. Breast Cancer Res Treat 123(1):245–255CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Varghese JS, Thompson DJ, Michailidou K, Lindstrom S, Turnbull C, Brown J, Leyland J, Warren RM, Luben RN, Loos RJ et al (2012) Mammographic breast density and breast cancer: evidence of a shared genetic basis. Cancer Res 72(6):1478–1484CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Vachon CM, Scott CG, Fasching PA, Hall P, Tamimi RM, Li J, Stone J, Apicella C, Odefrey F, Gierach GL et al (2012) Common breast cancer susceptibility variants in LSP1 and RAD51L1 are associated with mammographic density measures that predict breast cancer risk. Cancer Epidemiol Biomark Prev 21(7):1156–1166CrossRefGoogle Scholar
  24. 24.
    Stone J, Thompson DJ, Dos Santos Silva I, Scott C, Tamimi RM, Lindstrom S, Kraft P, Hazra A, Li J, Eriksson L et al (2015) Novel associations between common breast cancer susceptibility variants and risk-predicting mammographic density measures. Cancer Res 75(12):2457–2467CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lindstrom S, Thompson DJ, Paterson AD, Li J, Gierach GL, Scott C, Stone J, Douglas JA, dos-Santos-Silva I, Fernandez-Navarro P et al (2014) Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk. Nat Commun 5:5303CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Lindstrom S, Vachon CM, Li J, Varghese J, Thompson D, Warren R, Brown J, Leyland J, Audley T, Wareham NJ et al (2011) Common variants in ZNF365 are associated with both mammographic density and breast cancer risk. Nat Genet 43(3):185–187CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Schedin P (2006) Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer 6(4):281–291CrossRefPubMedGoogle Scholar
  28. 28.
    Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Vanderweele TJ, Vansteelandt S (2010) Odds ratios for mediation analysis for a dichotomous outcome. Am J Epidemiol 172(12):1339–1348CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Vachon CM, Pankratz VS, Scott CG, Maloney SD, Ghosh K, Brandt KR, Milanese T, Carston MJ, Sellers TA (2007) Longitudinal trends in mammographic percent density and breast cancer risk. Cancer Epidemiol Biomark Prev 16(5):921–928CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Megan S. Rice
    • 1
    Email author
  • Rulla M. Tamimi
    • 2
    • 3
  • Kimberly A. Bertrand
    • 4
  • Christopher G. Scott
    • 5
  • Matthew R. Jensen
    • 5
  • Aaron D. Norman
    • 5
  • Daniel W. Visscher
    • 6
  • Yunn-Yi Chen
    • 7
  • Kathleen R. Brandt
    • 8
  • Fergus J. Couch
    • 5
  • John A. Shepherd
    • 9
  • Bo Fan
    • 9
  • Fang-Fang Wu
    • 5
  • Lin Ma
    • 10
  • Laura C. Collins
    • 11
  • Steven R. Cummings
    • 12
  • Karla Kerlikowske
    • 13
  • Celine M. Vachon
    • 5
  1. 1.Clinical and Translational Epidemiology Unit, Department of MedicineMassachusetts General Hospital/Harvard Medical SchoolBostonUSA
  2. 2.Channing Division of Network MedicineBrigham and Women’s Hospital/Harvard Medical SchoolBostonUSA
  3. 3.Department of EpidemiologyHarvard T.H. Chan School of Public HealthBostonUSA
  4. 4.Slone Epidemiology Center, Boston UniversityBostonUSA
  5. 5.Department of Health Sciences ResearchMayo ClinicRochesterUSA
  6. 6.Department of Anatomic PathologyMayo ClinicRochesterUSA
  7. 7.Department of PathologyUniversity of CaliforniaSan FranciscoUSA
  8. 8.Department of RadiologyMayo ClinicRochesterUSA
  9. 9.Department of RadiologyUniversity of CaliforniaSan FranciscoUSA
  10. 10.Department of MedicineUniversity of CaliforniaSan FranciscoUSA
  11. 11.Department of PathologyHarvard Medical School, Beth Israel Deaconess Medical CenterBostonUSA
  12. 12.San Francisco Coordinating Center, California Pacific Medical Center Research InstituteSan FranciscoUSA
  13. 13.Departments of Epidemiology and Biostatistics and General Internal Medicine Section, Department of Veterans AffairsUniversity of CaliforniaSan FranciscoUSA

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