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Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials

Educational Objective
To understand the long-term benefits and risks of menopausal hormone therapy.
1 Credit CME
Key Points

Question  What is the association of estrogen plus progestin or estrogen alone with breast cancer incidence and breast cancer mortality?

Findings  In long-term follow up of 2 placebo-controlled randomized clinical trials involving 27 347 postmenopausal women, prior randomized use of conjugated equine estrogen (CEE), compared with placebo, among women with prior hysterectomy was significantly associated with lower risk of breast cancer (annualized incidence, 0.30% vs 0.37%; hazard ratio [HR], 0.78); and breast cancer mortality (annualized mortality, 0.031% vs 0.046%; HR, 0.60), whereas prior randomized use of CEE plus medroxyprogesterone acetate (MPA), compared with placebo, among women with an intact uterus, was significantly associated with higher risk of breast cancer (annualized incidence, 0.45% vs 0.36%; HR, 1.28) and no significant difference in breast cancer mortality (annualized mortality, 0.045% vs 0.035%; HR, 1.35).

Meaning  Among postmenopausal women, prior randomized use of CEE in women with prior hysterectomy was significantly associated with a lower risk of breast cancer incidence and mortality, whereas prior randomized use of CEE plus MPA in women with an intact uterus was significantly associated with a higher risk of breast cancer incidence and no significant difference in breast cancer mortality.

Abstract

Importance  The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials.

Objective  To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women’s Health Initiative clinical trials.

Design, Setting, and Participants  Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017.

Interventions  In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years’ median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years’ median intervention duration.

Main Outcomes and Measures  The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer.

Results  Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93; P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P < .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95; P= .11).

Conclusions and Relevance  In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.

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Article Information

Corresponding Author: Rowan T. Chlebowski, MD, PhD, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, 1124 W Carson St, Bldg N-18, Torrance, CA 90502 (rowanchlebowski@gmail.com).

Accepted for Publication: May 18, 2020.

Author Contributions: Mr Aragaki and Dr Chlebowski had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Chlebowski, Aragaki, Manson, Johnson, Cauley, Prentice.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Chlebowski, Aragaki, Manson, Stefanick.

Critical revision of the manuscript for important intellectual content: Chlebowski, Anderson, Manson, Pan, Barrington, Kuller, Simon, Lane, Johnson, Rohan, Gass, Cauley, Paskett, Sattari, Prentice.

Statistical analysis: Aragaki, Prentice.

Obtained funding: Anderson, Johnson, Prentice.

Administrative, technical, or material support: Chlebowski, Manson, Johnson, Cauley.

Supervision: Chlebowski, Anderson, Stefanick, Johnson, Cauley, Paskett, Prentice.

Conflict of Interest Disclosures: Dr Chlebowski reported receiving personal fees from Novartis, Pfizer, Amgen, Astra Zeneca, Immunomedics, Genentech, and Puma during the conduct of the study. Dr Anderson reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study; research funding from Mars Symbioscience, via a subcontract from Brigham and Women's Hospital, to serve as a data coordinating center for another chronic disease prevention. Dr Manson reported receiving grants from National Institutes of Health. Dr Johnson reported receiving grants from the NHLBI during the conduct of the study. Dr Paskett reported receiving grants from Pfizer, Merck, and FoxConn TechnologyGroup, held stock in Pfizer until April 2018, Breast Cancer Research Foundation, received grants from the Susan J. Komen Foundation. Dr Prentice reported receiving grants from the NHLBI during the conduct of the study. No other disclosures were reported.

Funding/Support: The Women’s Health Initiative program is supported by the NHLBI, National Institutes of Health, Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221.

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Women’s Health Initiative Investigators: Program Office: Jacques Rossouw, Shari Ludlum, Joan McGowan, Leslie Ford, and Nancy Geller, NHLBI, Bethesda, Maryland; Clinical Coordinating Center, Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg, Fred Hutchinson Cancer Research Center, Seattle, Washington; Investigators: JoAnn E. Manson, Brigham and Women's Hospital, Harvard Medical School; Barbara V. Howard, MedStar Health Research Institute and Howard University; Marcia L. Stefanick, Stanford Prevention Research Center; Rebecca Jackson, The Ohio State University; Cynthia A. Thomson, University of Arizona, Tucson and Phoenix; Jean Wactawski-Wende, University at Buffalo; Marian Limacher, University of Florida, Gainesville and Jacksonville; Jennifer Robinson, University of Iowa, Iowa City and Davenport; Lewis Kuller, University of Pittsburgh; Sally Shumaker, Wake Forest University School of Medicine; and Robert Brunner, University of Nevada, Reno; and Women’s Health Initiative Memory Study: Mark Espeland, Wake Forest University School of Medicine.

Meeting Presentation: Some of the findings were presented at the San Antonio Breast Cancer Symposium, San Antonio, Texas, on December 13, 2019, initially at an American Association for Cancer Research–sponsored press conference and followed by a meeting presentation (abstract oral session GS5).

Additional Contributions: We thank the Women’s Health Initiative investigators, staff, and trial participants for their outstanding dedication and commitment.

Additional information: A full list of all the investigators who have contributed to Women’s Health Initiative science appears at http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf.

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