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Randomized trials of estrogen-alone and breast cancer incidence: a meta-analysis

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Abstract

Purpose

In the Women’s Health initiative (WHI) randomized clinical trial, conjugated equine estrogen (CEE)-alone significantly reduced breast cancer incidence (P = 0.005). As cohort studies had opposite findings, other randomized clinical trials were identified to conduct a meta-analysis of estrogen-alone influence on breast cancer incidence.

Methods

We conducted literature searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analysis and reviews. In the meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, the corresponding log-RR = (O – E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP.

Results

Findings from 10 randomized trials included 14,282 participants and 591 incident breast cancers. In 9 smaller trials, with 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) (RR 0.65 95% CI 0.38–1.11, P = 0.12). For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34–1.16, P = 0.15. Combining the 10 trials, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo (overall RR 0.77 95% CI 0.65–0.91, P = 0.002).

Conclusion

The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use significantly reduces breast cancer incidence.

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Data availability

All the data are available from the sources cited in the manuscript.

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Acknowledgements

We acknowledge the commitment of the WHI investigators, staff, and the trial participants. Program Office: Jacques Roscoe, Shari Ludlum, Dale Burden, Joan McGowan, Leslie Ford, and Nancy Geller (National Heart, Lung, and Blood Institute, Bethesda, MD) Clinical Coordinating Center: Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kopperberg (Fred Hutchinson Cancer Research Center, Seattle, WA) Investigators and Academic Centers: JoAnn E. Manson (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA); Barbara V. Howard (MedStar Health Research Institute/Howard University, Washington, DC); Marcia L. Stefanick (Stanford Prevention Research Center, Stanford, CA); Rebecca Jackson (The Ohio State University, Columbus, OH); Cynthia A. Thompson (University of Arizona, Tucson/Phoenix, AZ); Jean Wactawski-Wende (University at Buffalo, Buffalo, NY); Marian Limacher (University of Florida, Gainesville/Jacksonville, FL); Robert Wallace (University of Iowa, Iowa City/Davenport, IA); Lewis Kuller (University of Pittsburgh, Pittsburgh, PA); Rowan T Chlebowski (The Lundquist Institute, Torrance, CA; and Sally Shumaker (Wake Forest University School of Medicine, Winston-Salem, NC).

A full list of all the investigators who have contributed to WHI science can be retrieved at: https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator %20Long%20List.pdf.

Funding

The development of this paper is partially supported by the National Cancer Institute grants R01 CA119171 and R01 CA10921. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C.

Author information

Authors and Affiliations

  1. The Lundquist Institute, 1124 W. Carson Street, Torrance, CA, USA

    Rowan T. Chlebowski

  2. Fred Hutchinson Cancer Center, Seattle, WA, USA

    Aaron K. Aragaki

  3. Kaiser Permanente Southern California, Downey, CA, USA

    Kathy Pan

  4. City of Hope National Medical Center, Duarte, CA, USA

    Joanne E. Mortimer, Sayeh Lavasani & Rebecca A. Nelson

  5. University of Tennessee Health Science Center, Memphis, TN, USA

    Karen C. Johnson

  6. University at Buffalo, Buffalo, NY, USA

    Jean Wactawski-Wende

  7. Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA

    Dorothy Lane

  8. Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Meryl S. LeBoff & JoAnn E. Manson

Authors
  1. Rowan T. Chlebowski
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Contributions

Rowan Chlebowski and Aaron Aragaki contributed to the study concept and design. Aaron Aragaki performed data collection. Both Rowan Chlebowski and Aaron Aragaki contributed to the first draft of the manuscript and provided the statistical analysis. All authors provided critical manuscript review and revision for important intellectual content. Rowan Chlebowski, Karen Johnson, Jean Wactawski-Wende, Dorothy Lane, and JoAnn Manson obtained funding. All authors read and approved the final manuscript.

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Correspondence to Rowan T. Chlebowski.

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Chlebowski, R.T., Aragaki, A.K., Pan, K. et al. Randomized trials of estrogen-alone and breast cancer incidence: a meta-analysis. Breast Cancer Res Treat (2024). https://doi.org/10.1007/s10549-024-07307-9

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