Breast Cancer Research and Treatment

, Volume 163, Issue 2, pp 363–373 | Cite as

Estrogen–progestin use and breast cancer characteristics in lean and overweight postmenopausal women

  • Olof J. Kjartansdottir
  • Lara G. Sigurdardottir
  • Elinborg J. Olafsdottir
  • Jon G. Jonasson
  • Giske Ursin
  • Laufey TryggvadottirEmail author



Breast cancer associated with estrogen–progestin (EP) therapy may have more favorable characteristics than cancer in never users, but results are conflicting. It is not well known either whether Body Mass Index (BMI) modifies this association. We investigated breast cancer characteristics in EP users for lean (BMI < 25 kg/m2) and overweight women (BMI ≥ 25 kg/m2).


The Icelandic Cancer Detection Clinic cohort, with information on breast cancer risk factors for 90% of Icelandic women, was linked with the population-based Icelandic Cancer Registry. A total of 781 women with invasive breast cancer diagnosed 51 years or older were matched with 7761 controls from the cohort. Conditional logistic regression was used for estimating adjusted odds ratios (OR) and 95% confidence intervals (CI) according to tumor characteristics, stratified by BMI. Polytomous logistic regression was applied in a case-only analysis for testing whether the risk associated with EP use differed according to tumor characteristics.


Ever EP users had a twofold higher risk of breast cancer compared with never users (OR 2.05, 95% CI 1.71–2.45). In lean women, EP use was significantly less likely to be associated with grade 2 or 3 tumors than grade 1 tumors, contrary to overweight women for whom risk was increased irrespective of grade. EP use in overweight women was associated with a higher risk of lobular than ductal cancer (OR 2.75, 95% CI 1.29–5.87).


Among lean EP users, tumor characteristics were more favorable than among never users. This effect was not observed for overweight women.


Menopausal hormone therapy Breast cancer Body Mass Index Tumor characteristics Estrogen Progesterone 



Body Mass Index


Icelandic Cancer Detection Clinic


Confidence interval






Estrogen receptor-positive/negative


Hormone therapy


Icelandic Cancer Registry


Odds ratio


Progesterone receptor-positive/negative



We are grateful to Dr. Jens Gudmundsson, Department of Obstetrics and Gynecology, University Hospital, Reykjavık, for valuable help in the preparatory phase of this study and to the women who participated in the CDC study. The project was supported by the Icelandic Cancer Society.


This study was funded by the Icelandic Cancer Society.

Compliance with ethical standards

Ethical approval

Approval was obtained for this study from the Bioethics Committee of Iceland (VSN-15-003) and the Icelandic Data Protection Authority (2014121741AT).


  1. 1.
    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. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 350(9084):1047–1059CrossRefGoogle Scholar
  2. 2.
    Ross RK, Paganini-Hill A, Wan PC, Pike MC (2000) Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 92(4):328–332CrossRefPubMedGoogle Scholar
  3. 3.
    Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A, Investigators WHI (2003) Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 289(24):3243–3253. doi: 10.1001/jama.289.24.3243 CrossRefPubMedGoogle Scholar
  4. 4.
    Beral V, Million Women Study C (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362(9382):419–427CrossRefGoogle Scholar
  5. 5.
    Beral V, Reeves G, Bull D, Green J, Million Women Study C (2011) Breast cancer risk in relation to the interval between menopause and starting hormone therapy. J Natl Cancer Inst 103(4):296–305. doi: 10.1093/jnci/djq527 CrossRefGoogle Scholar
  6. 6.
    Chlebowski RT, Anderson GL, Aragaki AK, Prentice R (2016) Breast cancer and menopausal hormone therapy by race/ethnicity and body mass index. J Natl Cancer Inst. doi: 10.1093/jnci/djv327 Google Scholar
  7. 7.
    Lyytinen H, Pukkala E, Ylikorkala O (2009) Breast cancer risk in postmenopausal women using estradiol-progestogen therapy. Obstet Gynecol 113(1):65–73. doi: 10.1097/AOG.0b013e31818e8cd6 CrossRefPubMedGoogle Scholar
  8. 8.
    Saxena T, Lee E, Henderson KD, Clarke CA, West D, Marshall SF, Deapen D, Bernstein L, Ursin G (2010) Menopausal hormone therapy and subsequent risk of specific invasive breast cancer subtypes in the California Teachers Study. Cancer Epidemiol Biomark Prev 19(9):2366–2378. doi: 10.1158/1055-9965.EPI-10-0162 CrossRefGoogle Scholar
  9. 9.
    Chlebowski RT, Anderson GL (2014) Menopausal hormone therapy and cancer: changing clinical observations of target site specificity. Steroids 90:53–59. doi: 10.1016/j.steroids.2014.06.001 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Holli K, Isola J, Cuzick J (1998) Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. J Clin Oncol 16(9):3115–3120CrossRefPubMedGoogle Scholar
  11. 11.
    Ursin G, Tseng CC, Paganini-Hill A, Enger S, Wan PC, Formenti S, Pike MC, Ross RK (2002) Does menopausal hormone replacement therapy interact with known factors to increase risk of breast cancer? J Clin Oncol 20(3):699–706CrossRefPubMedGoogle Scholar
  12. 12.
    Newcomb PA, Egan KM, Trentham-Dietz A, Titus-Ernstoff L, Baron JA, Hampton JM, Stampfer MJ, Willett WC (2008) Prediagnostic use of hormone therapy and mortality after breast cancer. Cancer Epidemiol Biomark Prev 17(4):864–871. doi: 10.1158/1055-9965.EPI-07-0610 CrossRefGoogle Scholar
  13. 13.
    Christante D, Pommier S, Garreau J, Muller P, LaFleur B, Pommier R (2008) Improved breast cancer survival among hormone replacement therapy users is durable after 5 years of additional follow-up. Am J Surg 196(4):505–511. doi: 10.1016/j.amjsurg.2008.06.023 CrossRefPubMedGoogle Scholar
  14. 14.
    Chlebowski RT, Anderson GL (2012) Changing concepts: menopausal hormone therapy and breast cancer. J Natl Cancer Inst 104(7):517–527. doi: 10.1093/jnci/djs014 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, Manson JE, Stefanick ML, Ockene J, Sarto GE, Johnson KC, Wactawski-Wende J, Ravdin PM, Schenken R, Hendrix SL, Rajkovic A, Rohan TE, Yasmeen S, Prentice RL, Investigators WHI (2010) Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 304(15):1684–1692. doi: 10.1001/jama.2010.1500 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chlebowski RT, Manson JE, Anderson GL, Cauley JA, Aragaki AK, Stefanick ML, Lane DS, Johnson KC, Wactawski-Wende J, Chen C, Qi L, Yasmeen S, Newcomb PA, Prentice RL (2013) Estrogen plus progestin and breast cancer incidence and mortality in the women’s health initiative observational study. J Natl Cancer Inst 105(8):526–535. doi: 10.1093/jnci/djt043 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Roman M, Graff-Iversen S, Weiderpass E, Vangen S, Sakshaug S, Hofvind S, Ursin G (2016) Postmenopausal hormone therapy and breast cancer prognostic characteristics: a linkage between nationwide registries. Cancer Epidemiol Biomark Prev 25(11):1464–1473. doi: 10.1158/1055-9965.EPI-16-0240 CrossRefGoogle Scholar
  18. 18.
    Kamineni A, Anderson ML, White E, Taplin SH, Porter P, Ballard-Barbash R, Malone K, Buist DS (2013) Body mass index, tumor characteristics, and prognosis following diagnosis of early-stage breast cancer in a mammographically screened population. Cancer Causes Control 24(2):305–312. doi: 10.1007/s10552-012-0115-7 CrossRefPubMedGoogle Scholar
  19. 19.
    Chan DS, Vieira AR, Aune D, Bandera EV, Greenwood DC, McTiernan A, Navarro Rosenblatt D, Thune I, Vieira R, Norat T (2014) Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol 25(10):1901–1914. doi: 10.1093/annonc/mdu042 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Rosenberg L, Czene K, Hall P (2009) Obesity and poor breast cancer prognosis: an illusion because of hormone replacement therapy? Br J Cancer 100(9):1486–1491. doi: 10.1038/sj.bjc.6605025 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Armannsdottir B, Tryggvadottir L, Jonasson JG, Olafsdottir EJ, Gudmundsson JA (2004) Use of hormone replacement therapy by Icelandic women in the years 1996-2001. Laeknabladid 90(6):471–477PubMedGoogle Scholar
  22. 22.
    Thorbjarnardottir T, Olafsdottir EJ, Valdimarsdottir UA, Olafsson O, Tryggvadottir L (2014) Oral contraceptives, hormone replacement therapy and breast cancer risk: a cohort study of 16 928 women 48 years and older. Acta Oncol 53(6):752–758. doi: 10.3109/0284186X.2013.878471 CrossRefPubMedGoogle Scholar
  23. 23.
    Sigurdardottir LG, Jonasson JG, Stefansdottir S, Jonsdottir A, Olafsdottir GH, Olafsdottir EJ, Tryggvadottir L (2012) Data quality at the Icelandic Cancer Registry: comparability, validity, timeliness and completeness. Acta Oncol 51(7):880–889. doi: 10.3109/0284186X.2012.698751 CrossRefPubMedGoogle Scholar
  24. 24.
    Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J, Writing Group for the Women’s Health Initiative I (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(3):321–333CrossRefPubMedGoogle Scholar
  25. 25.
    Rothman KJ (2002) Epidemiology an introduction. Oxford University Press, New YorkGoogle Scholar
  26. 26.
    Pike MC, Ross RK, Spicer DV (1998) Problems involved in including women with simple hysterectomy in epidemiologic studies measuring the effects of hormone replacement therapy on breast cancer risk. Am J Epidemiol 147(8):718–721CrossRefPubMedGoogle Scholar
  27. 27.
    Jones ME, Schoemaker MJ, Wright L, McFadden E, Griffin J, Thomas D, Hemming J, Wright K, Ashworth A, Swerdlow AJ (2016) Menopausal hormone therapy and breast cancer: what is the true size of the increased risk? Br J Cancer 115(5):607–615. doi: 10.1038/bjc.2016.231 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Munsell MF, Sprague BL, Berry DA, Chisholm G, Trentham-Dietz A (2014) Body mass index and breast cancer risk according to postmenopausal estrogen-progestin use and hormone receptor status. Epidemiol Rev 36:114–136. doi: 10.1093/epirev/mxt010 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Suzuki R, Orsini N, Saji S, Key TJ, Wolk A (2009) Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status—a meta-analysis. Int J Cancer 124(3):698–712. doi: 10.1002/ijc.23943 CrossRefPubMedGoogle Scholar
  30. 30.
    Huang Z, Hankinson SE, Colditz GA, Stampfer MJ, Hunter DJ, Manson JE, Hennekens CH, Rosner B, Speizer FE, Willett WC (1997) Dual effects of weight and weight gain on breast cancer risk. JAMA 278(17):1407–1411CrossRefPubMedGoogle Scholar
  31. 31.
    Lahmann PH, Hoffmann K, Allen N, van Gils CH, Khaw KT, Tehard B, Berrino F, Tjonneland A, Bigaard J, Olsen A, Overvad K, Clavel-Chapelon F, Nagel G, Boeing H, Trichopoulos D, Economou G, Bellos G, Palli D, Tumino R, Panico S, Sacerdote C, Krogh V, Peeters PH, Bueno-de-Mesquita HB, Lund E, Ardanaz E, Amiano P, Pera G, Quiros JR, Martinez C, Tormo MJ, Wirfalt E, Berglund G, Hallmans G, Key TJ, Reeves G, Bingham S, Norat T, Biessy C, Kaaks R, Riboli E (2004) Body size and breast cancer risk: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 111(5):762–771. doi: 10.1002/ijc.20315 CrossRefPubMedGoogle Scholar
  32. 32.
    Neuhouser ML, Aragaki AK, Prentice RL, Manson JE, Chlebowski R, Carty CL, Ochs-Balcom HM, Thomson CA, Caan BJ, Tinker LF, Urrutia RP, Knudtson J, Anderson GL (2015) Overweight, obesity, and postmenopausal invasive breast cancer risk: a secondary analysis of the women’s health initiative randomized clinical trials. JAMA Oncol 1(5):611–621. doi: 10.1001/jamaoncol.2015.1546 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ligibel J (2011) Obesity and breast cancer. Oncology 25(11):994–1000PubMedGoogle Scholar
  34. 34.
    Reeves GK, Beral V, Green J, Gathani T, Bull D, Million Women Study C (2006) Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol 7(11):910–918. doi: 10.1016/S1470-2045(06)70911-1 CrossRefPubMedGoogle Scholar
  35. 35.
    Dossus L, Benusiglio PR (2015) Lobular breast cancer: incidence and genetic and non-genetic risk factors. Breast Cancer Res 17:37. doi: 10.1186/s13058-015-0546-7 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Korhonen T, Huhtala H, Holli K (2004) A comparison of the biological and clinical features of invasive lobular and ductal carcinomas of the breast. Breast Cancer Res Treat 85(1):23–29. doi: 10.1023/B:BREA.0000021038.97593.8b CrossRefPubMedGoogle Scholar
  37. 37.
    Arpino G, Bardou VJ, Clark GM, Elledge RM (2004) Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome. Breast Cancer Res 6(3):R149–156. doi: 10.1186/bcr767 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Li CI, Malone KE, Daling JR (2006) Interactions between body mass index and hormone therapy and postmenopausal breast cancer risk (United States). Cancer Causes Control 17(5):695–703. doi: 10.1007/s10552-005-0001-7 CrossRefPubMedGoogle Scholar
  39. 39.
    Hou N, Hong S, Wang W, Olopade OI, Dignam JJ, Huo D (2013) Hormone replacement therapy and breast cancer: heterogeneous risks by race, weight, and breast density. J Natl Cancer Inst 105(18):1365–1372. doi: 10.1093/jnci/djt207 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Olof J. Kjartansdottir
    • 1
    • 2
    • 3
  • Lara G. Sigurdardottir
    • 4
  • Elinborg J. Olafsdottir
    • 3
  • Jon G. Jonasson
    • 5
    • 6
  • Giske Ursin
    • 7
    • 8
    • 9
  • Laufey Tryggvadottir
    • 3
    • 6
    Email author
  1. 1.Department of Clinical OncologyBeatson West of Scotland Cancer CentreGlasgowUK
  2. 2.Department of Internal MedicineLandspitali University HospitalReykjavikIceland
  3. 3.Icelandic Cancer RegistryIcelandic Cancer SocietyReykjavikIceland
  4. 4.Department of Education and PreventionIcelandic Cancer SocietyReykjavikIceland
  5. 5.Department of PathologyLandspitali University HospitalReykjavikIceland
  6. 6.Faculty of MedicineUniversity of IcelandReykjavikIceland
  7. 7.Cancer Registry of Norway, Institute of Population-Based Cancer ResearchOsloNorway
  8. 8.Department of Preventive MedicineUniversity of Southern CaliforniaLos AngelesUSA
  9. 9.Department of Nutrition, Institute of Basic Medical SciencesUniversity of OsloOsloNorway

Personalised recommendations