Original Study| Volume 22, ISSUE 2, e206-e213, February 2022

Breast Cancer Incidence and Mortality in Relation to Hormone Replacement Therapy Use Among Postmenopausal Women: Results From a Prospective Cohort Study

  • Yi Jiang
    Department of General Medicine and Geriatrics, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing, China
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  • QinLi Xie
    Address for correspondence: QinLi Xie, Physical Examination Center, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing 400015, China
    Physical Examination Center, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing, China
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  • Rong Chen
    Physical Examination Center, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing, China
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      Hormone replacement therapy (HRT) is associated with increased risk of breast cancer (BC), but little evidence assesses the effects of potential effect-modifiers on HRT-related BC. We sought to examine the relationship of different HRT types/method use and risk of BC in US postmenopausal women. In total, 689 BC cases and 81 BC deaths were identified during 372,210 person-years of follow-up. Cox regression and competing risk regression were used to estimate multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (95% CIs) by HRT status (never, former, current) for risk of BC incidence and mortality. The total current HRT use was associated with an increased risk of BC (HR current vs. never, 1.67; 95% CI, 1.33, 2.11), but did not associate with risk of death from BC (HR current vs. never, 0.85; 95% CI, 0.40, 1.78). Furthermore, underweight women (BMI <20 kg/m2, HR current vs. never, 12.05, 95% CI, 1.46, 99.75) were more likely to take increased risk of BC from HRT use compared to the obese (BMI >30 kg/m2, HR current vs never, 1.19; 95% CI, 0.73, 1.97). This study suggests that HRT use was associated with an altered risk of the occurrence of BC in the US postmenopausal women, especially for underweight women.



      PLCO (the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial), HRT (hormone replacement therapy), SQX (supplemental questionnaire), IQR (interquartile range), HR (hazards ratios), CI (confidence intervals)
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        • Lobo R.A.
        Hormone-replacement therapy: current thinking.
        Nat Rev Endocrinol. 2017; 13: 220-231
        • Houck J.A.
        What do these women want?": feminist responses to Feminine Forever, 1963-1980.
        Bull Hist Med. 2003; 77: 103-132
        • Stampfer M.J.
        • Colditz G.A.
        Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence.
        Prev Med. 1991; 20: 47-63
        • Manson J.E.
        • et al.
        Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women's Health Initiative Randomized Trials.
        Jama. 2017; 318: 927-938
        • Yaffe K.
        • Sawaya G.
        • Lieberburg I.
        • Grady D.
        Estrogen therapy in postmenopausal women: effects on cognitive function and dementia.
        JAMA. 1998; 279: 688-695
        • Miller K.D.
        • et al.
        Cancer treatment and survivorship statistics, 2019.
        CA Cancer J Clin. 2019; 69: 363-385
        • Carioli G.
        • et al.
        Trends and predictions to 2020 in breast cancer mortality in Europe.
        Breast (Edinburgh, Scotland). 2017; 36: 89-95
        • Wang K.
        • et al.
        Change in risk of breast cancer after receiving hormone replacement therapy by considering effect-modifiers: a systematic review and dose-response meta-analysis of prospective studies.
        Oncotarget. 2017; 8: 81109-81124
        • Greiser C.M.
        • Greiser E.M.
        • Dören M.
        Menopausal hormone therapy and risk of breast cancer: a meta-analysis of epidemiological studies and randomized controlled trials.
        Hum Reprod Update. 2005; 11: 561-573
        • Kim S.
        • Ko Y.
        • Lee H.J.
        • Lim J.E.
        Menopausal hormone therapy and the risk of breast cancer by histological type and race: a meta-analysis of randomized controlled trials and cohort studies.
        Breast Cancer Res Treat. 2018; 170: 667-675
        • 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
      1. 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. 1997; 350: 1047-1059
        • Mudhune G.H.
        • Armour M.
        • McBride K.A.
        Safety of menopausal hormone therapy in breast cancer survivors older than fifty at diagnosis: a systematic review and meta-analysis.
        Breast. 2019; 47: 43-55
        • Lyytinen H.
        • Pukkala E.
        • Ylikorkala O.
        Breast cancer risk in postmenopausal women using estradiol-progestogen therapy.
        Obstet Gynecol. 2009; 113: 65-73
        • Ewertz M.
        • et al.
        Hormone use for menopausal symptoms and risk of breast cancer. A Danish cohort study.
        Br J Cancer. 2005; 92: 1293-1297
        • Stahlberg C.
        • et al.
        Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe.
        Int J Cancer. 2004; 109: 721-727
        • Román M.
        • et al.
        Postmenopausal hormone therapy and the risk of breast cancer in Norway.
        Int J Cancer. 2016; 138: 584-593
        • Chlebowski R.T.
        • et al.
        Breast cancer after use of estrogen plus progestin and estrogen alone: analyses of data from 2 Women's Health Initiative Randomized Clinical Trials.
        JAMA Oncol. 2015; 1: 296-305
        • Fournier A.
        • et al.
        Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort.
        Breast Cancer Res Treat. 2014; 145: 535-543
        • Espié M.
        • et al.
        Breast cancer incidence and hormone replacement therapy: results from the MISSION study, prospective phase.
        Gynecol Endocrinol. 2007; 23: 391-397
        • Azam S.
        • et al.
        Hormone replacement therapy, mammographic density, and breast cancer risk: a cohort study.
        Cancer Causes Control. 2018; 29: 495-505
        • Ritte R.
        • et al.
        Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study.
        Breast Cancer Res. 2012; 14: R76
        • Beral V.
        • Reeves G.
        • Bull D.
        • Green J.
        Breast cancer risk in relation to the interval between menopause and starting hormone therapy.
        J Natl Cancer Inst. 2011; 103: 296-305
        • Jones M.E.
        • et al.
        Menopausal hormone therapy and breast cancer: what is the true size of the increased risk?.
        Br J Cancer. 2016; 115: 607-615
        • Kotsopoulos J.
        • et al.
        Risk factors for ductal and lobular breast cancer: results from the nurses' health study.
        Breast Cancer Res. 2010; 12: R106
        • Prorok P.C.
        • et al.
        Design of the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial.
        Control Clin Trials. 2000; 21: 273s-309s
        • Maldonado G.
        • Greenland S.
        Simulation study of confounder-selection strategies.
        Am J Epidemiol. 1993; 138: 923-936
        • Schoenfeld D.
        Chi-squared goodness-of-fit tests for the proportional hazards regression model.
        Biometrika. 1980; 67: 145-153
        • Santen R.J.
        • Yue W.
        • Heitjan D.F.
        Modeling of the growth kinetics of occult breast tumors: role in interpretation of studies of prevention and menopausal hormone therapy.
        Cancer Epidemiol Biomarkers Prev. 2012; 21: 1038-1048
        • Santen R.J.
        • Pinkerton J.
        • McCartney C.
        • Petroni G.R.
        Risk of breast cancer with progestins in combination with estrogen as hormone replacement therapy.
        J Clin Endocrinol Metab. 2001; 86: 16-23
      2. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial.
        JAMA. 1996; 275: 370-375
        • Lennon H.
        • Sperrin M.
        • Badrick E.
        • Renehan A.G.
        The obesity paradox in cancer: a review.
        Curr Oncol Rep. 2016; 18: 56
        • Chan D.S.M.
        • et al.
        Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies.
        Ann Oncol. 2014; 25: 1901-1914