Relationship between long durations and different regimens of hormone therapy and risk of breast cancer

JAMA. 2003 Jun 25;289(24):3254-63. doi: 10.1001/jama.289.24.3254.


Context: Women using combined estrogen and progestin hormone replacement therapy (CHRT) have an increased risk of breast cancer; however, data on use for long durations and on risk associated with patterns of use are lacking.

Objective: To evaluate relationships between durations and patterns of CHRT use and risk of breast cancer by histological type and hormone receptor status.

Design: Population-based case-control study.

Setting: Three counties in western Washington State.

Participants: Nine hundred seventy-five women 65-79 years of age diagnosed with invasive breast cancer from April 1, 1997, through May 31, 1999 (histology: 196 lobular cases, 656 ductal cases, 114 cases with other histological type, and 9 cases with an unspecified histological type; estrogen receptor (ER)/progesterone receptor (PR) status: 646 ER+/PR+ cases, 147 ER+/PR- cases, and 101 ER-/PR- cases [6 ER-/PR+ cases and 75 cases with unknown ER/PR status were not included in the analyses herein]) and 1007 population controls.

Main outcome measures: Risks of invasive lobular, ductal, ER+/PR+, ER+/PR-, and ER-/PR- breast carcinomas.

Results: Women using unopposed estrogen replacement therapy (ERT) (exclusive ERT use), even for 25 years or longer, had no appreciable increase in risk of breast cancer, although the associated odds ratios were not inconsistent with a possible small effect. Ever users of CHRT (includes CHRT users who also had used ERT) had a 1.7-fold (95% confidence interval [CI], 1.3-2.2) increased risk of breast cancer, including a 2.7-fold (95% CI, 1.7-4.3) increased risk of invasive lobular carcinoma, a 1.5-fold (95% CI, 1.1-2.0) increased risk of invasive ductal carcinoma, and a 2.0-fold (95% CI, 1.5-2.7) increased risk of ER+/PR+ breast cancers. The increase in risk was greatest in those using CHRT for longer durations (users for 5-14.9 years and >or=15 years had 1.5-fold [95% CI, 1.0-2.3] and 1.6-fold [95% CI, 1.0-2.6] increases in risk of invasive ductal carcinoma, respectively, and 3.7-fold [95% CI, 2.0-6.6] and 2.6-fold [95% CI, 1.3-5.3] increases in risk of invasive lobular carcinoma, respectively. Associations of similar magnitudes were seen among users of both sequential and continuous CHRT. Risks of ER+/PR- and ER-/PR- tumors were not increased by use of any form of hormone replacement therapy; however, small numbers of these tumors limited power to detect possible associations.

Conclusion: These data suggest that use of CHRT is associated with an increased risk of breast cancer, particularly invasive lobular tumors, whether the progestin component was taken in a sequential or in a continuous manner.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Breast Neoplasms / epidemiology*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / epidemiology
  • Carcinoma, Intraductal, Noninfiltrating / epidemiology
  • Carcinoma, Lobular / epidemiology
  • Case-Control Studies
  • Drug Administration Schedule
  • Estrogen Replacement Therapy* / adverse effects
  • Estrogens / therapeutic use*
  • Female
  • Humans
  • Logistic Models
  • Progestins / therapeutic use*
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Risk
  • SEER Program
  • Time Factors
  • Washington / epidemiology


  • Estrogens
  • Progestins
  • Receptors, Estrogen
  • Receptors, Progesterone