Breast Cancer Research and Treatment

, Volume 132, Issue 3, pp 1163–1171 | Cite as

Mammographic density, parity and age at first birth, and risk of breast cancer: an analysis of four case–control studies

  • Christy G. WoolcottEmail author
  • Karin Koga
  • Shannon M. Conroy
  • Celia Byrne
  • Chisato Nagata
  • Giske Ursin
  • Celine M. Vachon
  • Martin J. Yaffe
  • Ian Pagano
  • Gertraud Maskarinec


Mammographic density is strongly and consistently associated with breast cancer risk. To determine if this association was modified by reproductive factors (parity and age at first birth), data were combined from four case–control studies conducted in the United States and Japan. To overcome the issue of variation in mammographic density assessment among the studies, a single observer re-read all the mammograms using one type of interactive thresholding software. Logistic regression was used to estimate odds ratios (OR) while adjusting for other known breast cancer risk factors. Included were 1,699 breast cancer cases and 2,422 controls, 74% of whom were postmenopausal. A positive association between mammographic density and breast cancer risk was evident in every group defined by parity and age at first birth (OR per doubling of percent mammographic density ranged between 1.20 and 1.39). Nonetheless, the association appeared to be stronger among nulliparous than parous women (OR per doubling of percent mammographic density = 1.39 vs. 1.24; P interaction = 0.054). However, when examined by study location, the effect modification by parity was apparent only in women from Hawaii and when examined by menopausal status, it was apparent in postmenopausal, but not premenopausal, women. Effect modification by parity was not significant in subgroups defined by body mass index or ethnicity. Adjusting for mammographic density did not attenuate the OR for the association between parity and breast cancer risk by more than 16.4%, suggesting that mammographic density explains only a small proportion of the reduction in breast cancer risk associated with parity. In conclusion, this study did not support the hypothesis that parity modifies the breast cancer risk attributed to mammographic density. Even though an effect modification was found in Hawaiian women, no such thing was found in women from the other three locations.


Breast neoplasms Mammographic density Reproductive factors Epidemiology Risk factor Effect modification 



This research was supported by the National Cancer Institute, the US Department of Health and Human Services, grant number R03 CA 135699. CGW and SMC were supported for the completion of the study on this project through postdoctoral fellowships on grant number R25 CA 90956.

Conflict of Interest

Dr. Martin Yaffe is one of the founders of Matakina Technology, a manufacturer of software for the assessment of mammographic density. However, the software was not used in the present research, and neither the results nor the way the research was conducted has been influenced by Dr. Yaffe’s involvement in Matakina Technology.


  1. 1.
    Boyd NF, Martin LJ, Bronskill M, Yaffe MJ, Duric N, Minkin S (2010) Breast tissue composition and susceptibility to breast cancer. J Natl Cancer Inst 102(16):1224–1237PubMedCrossRefGoogle Scholar
  2. 2.
    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
  3. 3.
    Conroy SM, Woolcott CG, Byrne C, Nagata C, Ursin G, Vachon CM, Yaffe MJ, Koga K, Pagano I, Maskarinec G (2011) Mammographic density and risk of breast cancer by adiposity: an analysis of four case–control studies. Int J Cancer. doi: 10.1002/ijc.26205
  4. 4.
    Boyd NF, Martin LJ, Sun L, Guo H, Chiarelli A, Hislop G, Yaffe M, Minkin S (2006) Body size, mammographic density and breast cancer risk. Cancer Epidemiol Biomark Prev 15(11):2086–2092CrossRefGoogle Scholar
  5. 5.
    Martin LJ, Minkin S, Boyd NF (2009) Hormone therapy, mammographic density, and breast cancer risk. Maturitas 64(1):20–26PubMedCrossRefGoogle Scholar
  6. 6.
    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
  7. 7.
    Kerlikowske K, Cook AJ, Buist DS, Cummings SR, Vachon C, Vacek P, Miglioretti DL (2010) Breast cancer risk by breast density, menopause, and postmenopausal hormone therapy use. J Clin Oncol 28(24):3830–3837PubMedCrossRefGoogle Scholar
  8. 8.
    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):744–752PubMedCrossRefGoogle Scholar
  9. 9.
    van Gils CH, Hendriks JH, Otten JD, Holland R, Verbeek AL (2000) Parity and mammographic breast density in relation to breast cancer risk: indication of interaction. Eur J Cancer Prev 9(2):105–111PubMedCrossRefGoogle Scholar
  10. 10.
    Nechuta S, Paneth N, Velie EM (2010) Pregnancy characteristics and maternal breast cancer risk: a review of the epidemiologic literature. Cancer Causes Control 21(7):967–989PubMedCrossRefGoogle Scholar
  11. 11.
    Albrektsen G, Heuch I, Hansen S, Kvale G (2005) Breast cancer risk by age at birth, time since birth and time intervals between births: exploring interaction effects. Br J Cancer 92(1):167–175PubMedCrossRefGoogle Scholar
  12. 12.
    Collaborative Group on Hormonal Factors in Breast Cancer (2002) Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 360(9328):187–195CrossRefGoogle Scholar
  13. 13.
    Wu AH, Ursin G, Koh WP, Wang R, Yuan JM, Khoo KS, Yu MC (2008) Green tea, soy, and mammographic density in Singapore Chinese women. Cancer Epidemiol Biomark Prev 17(12):3358–3365CrossRefGoogle Scholar
  14. 14.
    Boyd N, Martin L, Gunasekara A, Melnichouk O, Maudsley G, Peressotti C, Yaffe M, Minkin S (2009) Mammographic density and breast cancer risk: evaluation of a novel method of measuring breast tissue volumes. Cancer Epidemiol Biomark Prev 18(6):1754–1762CrossRefGoogle Scholar
  15. 15.
    Haars G, van Noord PA, van Gils CH, Grobbee DE, Peeters PH (2005) Measurements of breast density: no ratio for a ratio. Cancer Epidemiol Biomark Prev 14(11 Pt 1):2634–2640CrossRefGoogle Scholar
  16. 16.
    Warren R, Skinner J, Sala E, Denton E, Dowsett M, Folkerd E, Healey CS, Dunning A, Doody D, Ponder B, Luben RN, Day NE, Easton D (2006) Associations among mammographic density, circulating sex hormones, and polymorphisms in sex hormone metabolism genes in postmenopausal women. Cancer Epidemiol Biomark Prev 15(8):1502–1508CrossRefGoogle Scholar
  17. 17.
    Stone J, Warren RM, Pinney E, Warwick J, Cuzick J (2009) Determinants of percentage and area measures of mammographic density. Am J Epidemiol 170(12):1571–1578PubMedCrossRefGoogle Scholar
  18. 18.
    Samimi G, Colditz GA, Baer HJ, Tamimi RM (2008) Measures of energy balance and mammographic density in the Nurses’ Health Study. Breast Cancer Res Treat 109(1):113–122PubMedCrossRefGoogle Scholar
  19. 19.
    Mackinnon DP, Fairchild AJ, Fritz MS (2007) Mediation analysis. Annu Rev Psychol 58:593–614PubMedCrossRefGoogle Scholar
  20. 20.
    Byng JW, Boyd NF, Fishell E, Jong RA, Yaffe MJ (1994) The quantitative analysis of mammographic densities. Phys Med Biol 39(10):1629–1638PubMedCrossRefGoogle Scholar
  21. 21.
    Maskarinec G, Pagano I, Lurie G, Wilkens LR, Kolonel LN (2005) Mammographic density and breast cancer risk: the multiethnic cohort study. Am J Epidemiol 162(8):743–752PubMedCrossRefGoogle Scholar
  22. 22.
    Ursin G, Ma H, Wu AH, Bernstein L, Salane M, Parisky YR, Astrahan M, Siozon CC, Pike MC (2003) Mammographic density and breast cancer in three ethnic groups. Cancer Epidemiol Biomark Prev 12(4):332–338Google Scholar
  23. 23.
    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
  24. 24.
    Nagata C, Matsubara T, Fujita H, Nagao Y, Shibuya C, Kashiki Y, Shimizu H (2005) Mammographic density and the risk of breast cancer in Japanese women. Br J Cancer 92(12):2102–2106PubMedCrossRefGoogle Scholar
  25. 25.
    Byng JW, Boyd NF, Little L, Lockwood G, Fishell E, Jong RA, Yaffe MJ (1996) Symmetry of projection in the quantitative analysis of mammographic images. Eur J Cancer Prev 5(5):319–327PubMedCrossRefGoogle Scholar
  26. 26.
    Desquilbet L, Mariotti F (2010) Dose–response analyses using restricted cubic spline functions in public health research. Stat Med 29(9):1037–1057Google Scholar
  27. 27.
    Szklo M, Nieto FJ (2000) Epidemiology: beyond the basics. Aspen Publishers, GaithersburgGoogle Scholar
  28. 28.
    Russo J, Hu YF, Yang X, Russo IH (2000) Developmental, cellular, and molecular basis of human breast cancer. J Natl Cancer Inst Monogr 2000(27):17–37Google Scholar
  29. 29.
    Li T, Sun L, Miller N, Nicklee T, Woo J, Hulse-Smith L, Tsao MS, Khokha R, Martin L, Boyd N (2005) The association of measured breast tissue characteristics with mammographic density and other risk factors for breast cancer. Cancer Epidemiol Biomark Prev 14(2):343–349CrossRefGoogle Scholar
  30. 30.
    Balogh GA, Heulings R, Mailo DA, Russo PA, Sheriff F, Russo IH, Moral R, Russo J (2006) Genomic signature induced by pregnancy in the human breast. Int J Oncol 28(2):399–410PubMedGoogle Scholar
  31. 31.
    Medina D (2005) Mammary developmental fate and breast cancer risk. Endocr Relat Cancer 12(3):483–495PubMedCrossRefGoogle Scholar
  32. 32.
    Tamburrini AL, Woolcott CG, Boyd NF, Yaffe MJ, Terry T, Yasui Y, Jones CA, Patten SB, Courneya KS, Friedenreich CM (2010) Associations between mammographic density and serum and dietary cholesterol. Breast Cancer Res Treat 125(1):181–189PubMedCrossRefGoogle Scholar
  33. 33.
    Hafeman D (2009) “Proportion explained”: a causal interpretation for standard measures of indirect effect. Am J Epidemiol 170(11):1443–1448PubMedCrossRefGoogle Scholar
  34. 34.
    Vacek PM, Geller BM (2004) A prospective study of breast cancer risk using routine mammographic breast density measurements. Cancer Epidemiol Biomark Prev 13(5):715–722Google Scholar
  35. 35.
    Jakes RW, Duffy SW, Ng FC, Gao F, Ng EH (2000) Mammographic parenchymal patterns and risk of breast cancer at and after a prevalence screen in Singaporean women. Int J Epidemiol 29(1):11–19PubMedCrossRefGoogle Scholar
  36. 36.
    Tice JA, Cummings SR, Ziv E, Kerlikowske K (2005) Mammographic breast density and the Gail model for breast cancer risk prediction in a screening population. Breast Cancer Res Treat 94(2):115–122PubMedCrossRefGoogle Scholar
  37. 37.
    Ma H, Luo J, Press MF, Wang Y, Bernstein L, Ursin G (2009) Is there a difference in the association between percent mammographic density and subtypes of breast cancer? Luminal A and triple-negative breast cancer. Cancer Epidemiol Biomark Prev 18(2):479–485CrossRefGoogle Scholar
  38. 38.
    Ma H, Bernstein L, Pike MC, Ursin G (2006) Reproductive factors and breast cancer risk according to joint estrogen and progesterone receptor status: a meta-analysis of epidemiological studies. Breast Cancer Res 8(4):R43PubMedCrossRefGoogle Scholar
  39. 39.
    Yang XR, Chang-Claude J, Goode EL, Couch FJ, Nevanlinna H, Milne RL et al (2011) Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies. J Natl Cancer Inst 103(3):250–263PubMedCrossRefGoogle Scholar
  40. 40.
    Dearth RK, Delgado DA, Hiney JK, Pathiraja T, Oesterreich S, Medina D, Dees WL, Lee AV (2010) Parity-induced decrease in systemic growth hormone alters mammary gland signaling: a potential role in pregnancy protection from breast cancer. Cancer Prev Res (Phila) 3(3):312–321CrossRefGoogle Scholar
  41. 41.
    Schedin P (2006) Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer 6(4):281–291PubMedCrossRefGoogle Scholar
  42. 42.
    Ghosh K, Brandt KR, Reynolds CA (2009) Histologic markers of mammographic breast density: core-needle biopsy tissue from healthy volunteers. Cancer Res 69(Suppl 2):263SGoogle Scholar
  43. 43.
    Wiseman BS, Werb Z (2002) Stromal effects on mammary gland development and breast cancer. Science 296(5570):1046–1049PubMedCrossRefGoogle Scholar
  44. 44.
    Passaperuma K, Warner E, Hill KA, Gunasekara A, Yaffe MJ (2010) Is mammographic breast density a breast cancer risk factor in women with BRCA mutations? J Clin Oncol 28(23):3779–3783PubMedCrossRefGoogle Scholar
  45. 45.
    Kotsuma Y, Tamaki Y, Nishimura T, Tsubai M, Ueda S, Shimazu K, Jin Kim S, Miyoshi Y, Tanji Y, Taguchi T, Noguchi S (2007) Quantitative assessment of mammographic density and breast cancer risk for Japanese women. Breast 17(1):27–35PubMedCrossRefGoogle Scholar
  46. 46.
    Duffy SW, Jakes RW, Ng FC, Gao F (2004) Interaction of dense breast patterns with other breast cancer risk factors in a case–control study. Br J Cancer 91(2):233–236PubMedGoogle Scholar
  47. 47.
    Tice JA, Cummings SR, Smith-Bindman R, Ichikawa L, Barlow WE, Kerlikowske K (2008) Using clinical factors and mammographic breast density to estimate breast cancer risk: development and validation of a new predictive model. Ann Intern Med 148(5):337–347PubMedGoogle Scholar
  48. 48.
    Chen J, Pee D, Ayyagari R, Graubard B, Schairer C, Byrne C, Benichou J, Gail MH (2006) Projecting absolute invasive breast cancer risk in white women with a model that includes mammographic density. J Natl Cancer Inst 98(17):1215–1226PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Christy G. Woolcott
    • 1
    Email author
  • Karin Koga
    • 2
  • Shannon M. Conroy
    • 2
  • Celia Byrne
    • 3
  • Chisato Nagata
    • 4
  • Giske Ursin
    • 5
  • Celine M. Vachon
    • 6
  • Martin J. Yaffe
    • 7
  • Ian Pagano
    • 2
  • Gertraud Maskarinec
    • 2
  1. 1.Departments of Obstetrics & Gynaecology and PediatricsDalhousie UniversityHalifaxCanada
  2. 2.University of Hawaii Cancer CenterHonoluluUSA
  3. 3.Georgetown Lombardi Comprehensive Cancer CenterWashingtonUSA
  4. 4.Gifu University Graduate School of MedicineGifuJapan
  5. 5.University of OsloOsloNorway
  6. 6.Mayo ClinicRochesterUSA
  7. 7.Sunnybrook Research InstituteTorontoCanada

Personalised recommendations