Research Article| Volume 79, ISSUE 4, P442-448, December 2014

Lifestyle influences on the association between pre-diagnostic hormone replacement therapy and breast cancer prognosis—Results from The Danish ‘Diet, Cancer and Health’ prospective cohort

Published:September 20, 2014DOI:



      The association between pre-diagnostic hormone replacement therapy (HRT) and breast cancer specific mortality as well as potential influences from other lifestyle factors on the association was investigated.

      Study design

      Female participants from the prospective cohort “Diet, Cancer, and Health” diagnosed with breast cancer (BC) were identified and their pre-diagnostic HRT use evaluated for association with tumour biology and breast cancer outcome in multivariate analysis.

      Main outcome measure

      Breast cancer specific mortality.


      Of the 1212 patients originally considered 1064 were included. Of these, 105 women died from breast cancer during a median follow-up of 6.3 years (range 0.2–14.3 years). In multivariate analyses women who used HRT at enrolment into the cohort study had 47% lower risk of dying from breast cancer as compared to women who had previously or never used HRT (adjusted HR: 0.53; 95% CI, 0.37–0.85). Pre-diagnostic HRT use was associated with smaller tumour size at the time of diagnosis and a higher frequency of receptor positive breast cancer. Paradoxically, a high pre-diagnostic intake of vitamin D supplements was associated with HRT use but also with a higher BC specific mortality (HR: 1.47; 95% CI, 1.07–2.00)


      HRT use at enrolment was associated with breast tumours of smaller size at the time of diagnosis and positive receptor status, and with a lower BC mortality. The found association between vitamin D from supplements and higher BC mortality warrants further exploration.



      HRT (hormone replacement therapy), BMI (body mass index)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Maturitas
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • World Cancer Research Fund/American Institute for Cancer Research
        Food, nutrition, physical activity, and the prevention of cancer: a global perspective.
        AICR, Washington, DC2007 ([report no.: 2nd])
        • Chlebowski R.T.
        • Hendrix S.L.
        • Langer R.D.
        • et al.
        Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial.
        JAMA. 2003; 289: 3243-3253
        • Rosenberg L.U.
        • Granath F.
        • Dickman P.W.
        • et al.
        Menopausal hormone therapy in relation to breast cancer characteristics and prognosis: a cohort study.
        Breast Cancer Res. 2008; 10: R78
        • Newcomb P.A.
        • Egan K.M.
        • Trentham-Dietz A.
        • et al.
        Prediagnostic use of hormone therapy and mortality after breast cancer.
        Cancer Epidemiol Biomark Prev. 2008; 17: 864-871
        • Nanda K.
        • Bastian L.A.
        • Schulz K.
        Hormone replacement therapy and the risk of death from breast cancer: a systematic review.
        Am J Obstet Gynecol. 2002; 186: 325-334
        • Schuetz F.
        • Diel I.J.
        • Pueschel M.
        • et al.
        Reduced incidence of distant metastases and lower mortality in 1072 patients with breast cancer with a history of hormone replacement therapy.
        Am J Obstet Gynecol. 2007; 196: 342-349
        • Sener S.F.
        • Winchester D.J.
        • Winchester D.P.
        • et al.
        The effects of hormone replacement therapy on postmenopausal breast cancer biology and survival.
        Am J Surg. 2009; 197: 403-407
        • Christante D.
        • Pommier S.
        • Garreau J.
        • Muller P.
        • LaFleur B.
        • Pommier R.
        Improved breast cancer survival among hormone replacement therapy users is durable after 5 years of additional follow-up.
        Am J Surg. 2008; 196: 505-511
        • Reding K.W.
        • Doody D.R.
        • McTiernan A.
        • et al.
        Age-related variation in the relationship between menopausal hormone therapy and the risk of dying from breast cancer.
        Breast Cancer Res Treat. 2011; 126: 749-761
        • Chlebowski R.T.
        • Anderson G.L.
        • Gass M.
        • et al.
        Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.
        JAMA. 2010; 304: 1684-1692
        • Chlebowski R.T.
        • Manson J.E.
        • Anderson G.L.
        • et al.
        Estrogen plus progestin and breast cancer incidence and mortality in the Women's Health Initiative Observational Study.
        J Natl Cancer Inst. 2013; 105: 526-535
        • Chlebowski R.T.
        • Anderson G.L.
        Changing concepts: menopausal hormone therapy and breast cancer.
        J Natl Cancer Inst. 2012; 104: 517-527
        • Baum M.
        Breast cancer survival and the use of HRT.
        Breast. 2005; 14: 178-180
        • Norman S.A.
        • Weber A.L.
        • Localio A.R.
        • et al.
        Hormone therapy and fatal breast cancer.
        Pharmacoepidemiol Drug Saf. 2010; 19: 440-447
        • Beral V.
        Breast cancer and hormone-replacement therapy in the Million Women Study.
        Lancet. 2003; 362: 419-427
        • Rosenberg L.
        • Czene K.
        • Hall P.
        Obesity and poor breast cancer prognosis: an illusion because of hormone replacement therapy?.
        Br J Cancer. 2009; 100: 1486-1491
        • Ding E.L.
        • Mehta S.
        • Fawzi W.W.
        • Giovannucci E.L.
        Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: reanalysis of Women's Health Initiative randomized trial.
        Int J Cancer. 2008; 122: 1690-1694
        • Tjonneland A.
        • Olsen A.
        • Boll K.
        • et al.
        Study design, exposure variables, and socioeconomic determinants of participation in Diet, Cancer and Health: a population-based prospective cohort study of 57,053 men and women in Denmark.
        Scand J Public Health. 2007; 35: 432-441
        • Storm H.H.
        • Michelsen E.V.
        • Clemmensen I.H.
        • Pihl J.
        The Danish Cancer Registry—history, content, quality and use.
        Dan Med Bull. 1997; 44: 535-539
        • Juel K.
        • Helweg-Larsen K.
        The Danish registers of causes of death.
        Dan Med Bull. 1999; 46: 354-357
        • Moller S.
        • Jensen M.B.
        • Ejlertsen B.
        • et al.
        The clinical database and the treatment guidelines of the Danish Breast Cancer Cooperative Group (DBCG); its 30-years experience and future promise.
        Acta Oncol. 2008; 47: 506-524
        • Sobin L.H.
        • Gospodarowicz M.K.
        • Wittekind C.
        International Union Against Cancer (UICC) TNM Classification of malignant tumors.
        7th ed. Wiley-Blackwell, Oxford, UK2013
        • Borgquist S.
        • Anagnostaki L.
        • Jirstrom K.
        • Landberg G.
        • Manjer J.
        Breast tumours following combined hormone replacement therapy express favourable prognostic factors.
        Int J Cancer. 2007; 120: 2202-2207
        • Sacchini V.
        • Zurrida S.
        • Andreoni G.
        • et al.
        Pathologic and biological prognostic factors of breast cancers in short- and long-term hormone replacement therapy users.
        Ann Surg Oncol. 2002; 9: 266-271
        • Hall P.
        • Ploner A.
        • Bjohle J.
        • et al.
        Hormone-replacement therapy influences gene expression profiles and is associated with breast-cancer prognosis: a cohort study.
        BMC Med. 2006; 4: 16
        • Saphner T.
        • Tormey D.C.
        • Gray R.
        Annual hazard rates of recurrence for breast cancer after primary therapy.
        J Clin Oncol. 1996; 14: 2738-2746
        • Brunner R.L.
        • Wactawski-Wende J.
        • Caan B.J.
        • et al.
        The effect of calcium plus vitamin D on risk for invasive cancer: results of the Women's Health Initiative (WHI) calcium plus vitamin D randomized clinical trial.
        Nutr Cancer. 2011; 63: 827-841
        • Rose A.A.
        • Elser C.
        • Ennis M.
        • Goodwin P.J.
        Blood levels of vitamin D and early stage breast cancer prognosis: a systematic review and meta-analysis.
        Breast Cancer Res Treat. 2013; 141: 331-339
        • Goldoni C.A.
        • Bonora K.
        • Ciatto S.
        • et al.
        Misclassification of breast cancer as cause of death in a service screening area.
        Cancer Causes Control. 2009; 20: 533-538