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Estrogen-alone therapy and invasive breast cancer incidence by dose, formulation, and route of delivery

findings from the WHI observational study

Shufelt, Chrisandra MD, MS, NCMP1; Bairey Merz, C. Noel MD1; Pettinger, Mary B. MS2; Choi, Lydia MD3; Chlebowski, Rowan MD, PhD4; Crandall, Carolyn J. MD, MS5; Liu, Simin MD, ScD6; Lane, Dorothy MD, MPH7; Prentice, Ross PhD2; Manson, JoAnn E. MD, DrPH8 for the Women's Health Initiative Investigators

doi: 10.1097/GME.0000000000001115
Original Articles

Objective: Research on the relationships between different hormone therapy doses, formulation and routes of delivery, and subsequent breast cancer incidence has been limited. This study directly compared different estrogen doses, formulations, and route of delivery of estrogen alone among women with a hysterectomy in relation to invasive breast cancer incidence.

Methods: The Women's Health Initiative Observational Study is a large multicenter prospective cohort study conducted at 40 US sites. Analyses included 26,525 postmenopausal women with a hysterectomy, aged 50 to 79 years, at study entry, recruited between September, 1993 and December, 1998, with annual follow-up through September 12, 2005.

Results: Average follow-up was 8.2 years. For conjugated equine estrogen (CEE) users, no difference was observed between low-dose CEE (<0.625 mg) compared with conventional-dose CEE (0.625 mg) for breast cancer (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.65, 1.48)]. Compared with conventional-dose CEE, transdermal estrogen was associated with a nonsignificant lower risk of invasive breast cancer (HR 0.75, 95% CI 0.47, 1.19). The low prevalence of transdermal use likely limited power for this comparison, and for a comparison of oral estradiol to conventional-dose CEE (HR 1.20, 95% CI 0.84, 1.39).

Conclusion: Our results indicate that invasive breast cancer risk did not differ appreciably in women with a hysterectomy using estrogen-alone when directly comparing different doses, formulations, and routes of delivery to the conventional oral CEE. These findings suggest that the lower breast cancer risk found in the WHI estrogen-alone trial may extend to lower doses of CEE. Additional research is needed to confirm these hypotheses.

1Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA

2Fred Hutchinson Cancer Research Center, Seattle, WA

3Karmanos Cancer Institute Wayne State University, Detroit, MI

4Department of Medical Oncology and Developmental Therapeutics, City of Hope National Medical Center, Duarte, CA

5Department of Medicine, University of California, Los Angeles, Los Angeles, CA

6Department of Epidemiology, Brown University, Providence, RI

7Department of Family, Population and Preventive Medicine, Stony Brook University School of Medicine, Stony Brook, NY

8Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Address correspondence to: Chrisandra Shufelt, MD, MS, NCMP, 8631 W. Third Street, Suite 740 East, Los Angeles, CA 90048. E-mail:

Received 24 December, 2017

Revised 12 February, 2018

Accepted 12 February, 2018

Presentation: This research was presented as an oral abstract at the 2016 North American Menopause Society annual meeting, Orlando, Florida, by Dr Shufelt.

Women's Health Initiative Investigators: A full listing of Women's Health Initiative investigators can be found at

Additional contributions: We thank the Women's Health Initiative investigators, staff, and study participants for their outstanding dedication and commitment.

Funding/support: The Women's Health Initiative program is funded by the National Heart, Lung, and Blood Institute, the National Institutes of Health, and the US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. This work was also supported by K23HL127262-01A1, GCRC grant MO1-RR00425 from the National Center for Research Resources, and the Edythe L. Broad Women's Heart Research Fellowship, Cedars-Sinai Medical Center, Los Angeles, California, and the Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles.

Financial disclosure/conflicts of interest: Dr Chlebowski reports receipt of consulting fees or honoraria from Novartis, Genentech, Amgen, and Astra-Zeneca, Novo Nordisk, and Genomic Health; fees for participation in review activities from Pfizer; payment for lectures from Novartis; and payment for educational activities from Educational Concepts Group. All other authors report no conflicts of interest/disclosures.

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© 2018 by The North American Menopause Society.