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Christopher I. Li, MD, PhD; Kathleen E. Malone, PhD; Peggy L. Porter, MD; Noel S. Weiss, MD, DrPH; Mei-Tzu C. Tang, PhD; Kara L. Cushing-Haugen, MS; Janet R. Daling, PhD

JAMA. 2003;289:3254-3263.

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 ≥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.

Author Affiliations: Division of Public Health Sciences (Drs Li, Malone, Weiss, Tang, and Daling, and Ms Cushing-Haugen) and Division of Human Biology (Dr Porter), Fred Hutchinson Cancer Research Center, Seattle, Wash; and Department of Epidemiology, School of Public Health and Community Medicine (Drs Li, Malone, Weiss, and Daling) and Department of Pathology, School of Medicine (Dr Porter), University of Washington, Seattle.

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