Use of postmenopausal hormone therapies and risk of histology- and hormone receptor-defined breast cancer: results from a 15-year prospective analysis of NIH-AARP cohort

Breast Cancer Res. 2020 Nov 25;22(1):129. doi: 10.1186/s13058-020-01365-9.


Background: Menopausal hormone therapy (MHT) increases breast cancer (BC) risk, but cohort studies largely consider use only at enrollment. Evidence is limited on how changes in MHT use alter the magnitude of risk, and whether risk varies between invasive and in situ cancer, by histology or by hormone receptor status.

Methods: We investigated the roles of estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT) on BC risk overall, by histology and estrogen receptor (ER) and progesterone receptor (PR) status, and on incidence of in situ disease, in the NIH-AARP cohort. Participants included 118,760 postmenopausal women (50-71 years), of whom 63.5% (n = 75,398) provided MHT use information at baseline in 1996 and in a follow-up survey in 2004, subsequent to the dissemination in 2002 of the Women's Health Initiative trial safety concerns regarding EPT. ET analyses included 50,476 women with hysterectomy (31,439 with follow-up data); EPT analyses included 68,284 women with intact uteri (43,959 with follow-up data). Adjusted hazard ratios (HRs) were estimated using Cox proportional hazards models using age as the time metric with follow-up through 2011.

Results: Eight thousand three hundred thirty-three incident BC cases were accrued, 2479 in women with follow-up data. BC risk was not elevated in current ET users at baseline (HR = 1.05, 95% confidence interval [CI] CI = 0.95-1.16) but was higher in women continuing use through 2004 (HR = 1.35, 95% CI = 1.04-1.75). Ever EPT use at baseline was associated with elevated BC risk overall (HR = 1.54 (1.44-1.64), with a doubling in risk for women with 10 or more years of use, for in situ disease, and across subtypes defined by histology and ER/PR status (all p < 0.004). Risk persisted in women who continued EPT through 2004 (HR = 1.80, 95% CI = 1.39-2.32). In contrast, no association was seen in women who discontinued EPT before 2004 (HR = 1.14, 95% CI = 0.99-1.30).

Conclusions: ET use was not associated with BC risk in this cohort, although excess risk was suggested in women who continued use through 2004. EPT use was linked to elevated in situ and invasive BC risk, and elevated risk across invasive BC histologic and hormone receptor-defined subtypes, with the highest risk for women who continued use through the 2004 follow-up survey.

Keywords: Breast cancer risk; Menopausal hormone therapy; NIH-AARP cohort.

Publication types

  • Observational Study
  • Research Support, N.I.H., Intramural

MeSH terms

  • Aged
  • Biomarkers, Tumor / analysis*
  • Biomarkers, Tumor / metabolism
  • Breast / pathology
  • Breast Neoplasms / chemically induced
  • Breast Neoplasms / epidemiology*
  • Breast Neoplasms / pathology
  • Estrogens / administration & dosage
  • Estrogens / adverse effects
  • Female
  • Follow-Up Studies
  • Hormone Replacement Therapy / adverse effects*
  • Hormone Replacement Therapy / methods
  • Humans
  • Hysterectomy / adverse effects
  • Incidence
  • Middle Aged
  • Postmenopause / drug effects*
  • Postmenopause / metabolism
  • Progestins / administration & dosage
  • Progestins / adverse effects
  • Prospective Studies
  • Receptors, Estrogen / analysis
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / analysis
  • Receptors, Progesterone / metabolism
  • Risk Assessment / statistics & numerical data
  • Risk Factors


  • Biomarkers, Tumor
  • Estrogens
  • Progestins
  • Receptors, Estrogen
  • Receptors, Progesterone