Diana S.M. Buist, PhD, MPH; Melissa L. Anderson, MS; Susan D. Reed, MD, MS, MPH; Erin J. Aiello Bowles, MPH; E. Dawn Fitzgibbons, MPH; Juleann C. Gandara, MD; Deborah Seger, BA; Katherine M. Newton, PhD
Note: The study team had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Acknowledgment: The authors thank Tammy Dodd, Linda Palmer, and Melissa Rabelhofer, as well as members of their advisory board: Hermien Watkins, Paula Hoffman, Deb Schiro, and Margrit Schubiger; members of the Data Safety and Monitoring Board: Susan Heckbert, Ben Anderson, Mary Anne Rossing, Robert D. Rosenberg, and Thomas Lumley; and Elizabeth Lin, the medical monitor. The authors also thank Robert Karl, Donna White, and Jo Ellen Callahan for their support for implementing this trial at Group Health. Finally, the authors thank Stephen Taplin, for his collaboration in getting this study funded when he was an investigator at Group Health Cooperative, and Rebecca Hughes for her editorial assistance.
Grant Support: The READ Trial was funded by the Department of Defense (DAMD17-03-1-0447). Study participants were recruited from the Group Health Breast Cancer Screening Program, which is funded by the National Cancer Institute (U01CA63731).
Potential Financial Conflicts of Interest: None disclosed.
Reproducible Research Statement:Study protocol: Available from Dr. Buist (e-mail, email@example.com). Statistical code: Available from Ms. Anderson (e-mail, Anderson.Melissa@ghc.org). Data set: Not available.
Requests for Single Reprints: Diana S.M. Buist, PhD, MPH, Group Health Center for Health Studies, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101-1448; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Buist and Newton, Ms. Anderson, Ms. Aiello Bowles, Ms. Fitzgibbons, and Ms. Seger: Group Health Center for Health Studies, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101-1448.
Dr. Reed: Obstetrics and Gynecology, Harborview Medical Center, Box 359865, Seattle, WA 98104-2499.
Dr. Gandara: Group Health Family Health Center, 125 16th Avenue East, Seattle, WA 98112.
Author Contributions: Conception and design: D.S.M. Buist, K.M. Newton.
Analysis and interpretation of the data: D.S.M. Buist, M.L. Anderson, S.D. Reed, E.J. Aiello Bowles, K.M. Newton.
Drafting of the article: D.S.M. Buist, M.L. Anderson, S.D. Reed, D. Seger.
Critical revision of the article for important intellectual content: D.S.M. Buist, M.L. Anderson, S.D. Reed, E.J. Aiello Bowles, K.M. Newton.
Final approval of the article: D.S.M. Buist, M.L. Anderson, S.D. Reed, E.J. Aiello Bowles, E.D. Fitzgibbons, J.C. Gandara, K.M. Newton.
Provision of study materials or patients: D.S.M. Buist, E.D. Fitzgibbons, J.C. Gandara.
Statistical expertise: D.S.M. Buist, M.L. Anderson.
Obtaining of funding: D.S.M. Buist.
Administrative, technical, or logistic support: D.S.M. Buist, E.D. Fitzgibbons, J.C. Gandara, D. Seger.
Collection and assembly of data: D.S.M. Buist, E.J. Aiello Bowles, E.D. Fitzgibbons, J.C. Gandara, D. Seger.
ClinicalTrials.gov registration number:NCT00117663.
Buist D., Anderson M., Reed S., Aiello Bowles E., Fitzgibbons E., Gandara J., Seger D., Newton K.; Short-Term Hormone Therapy Suspension and Mammography Recall: A Randomized Trial. Ann Intern Med. 2009;150:752-765. doi: 10.7326/0003-4819-150-11-200906020-00003
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Published: Ann Intern Med. 2009;150(11):752-765.
Without population-based evidence, some clinicians recommend short-term suspension of hormone therapy to improve the performance of mammography. Hormone therapy increases breast density, and abnormal screening mammograms are more common among women with denser breasts and among women using hormone therapy.
To test whether 1 to 2 months of hormone therapy suspension before screening mammography decreases additional mammographic imaging (recall) in women age 45 to 80 years.
3-group randomized, controlled trial.
Integrated health plan in western Washington from 2004 to 2007.
1704 women age 45 to 80 years who used hormone therapy at their most recent screening (index) mammography, were due for screening (study) mammography, and were still using hormone therapy.
Block random assignment (by breast density and hormone therapy type) to no hormone therapy suspension (nÂ = 567) or suspension for 1 month (nÂ = 570) or 2 months (nÂ = 567) before study mammography. One blinded expert radiologist interpreted all mammograms.
Recall was the primary outcome, and change in mammographic breast density (percentage and dense area) between the index and study mammograms was the secondary outcome.
Mammography recall rates were 11.3% (61 of 542 women in the no-suspension group), 12.3% (50 of 478 women in the 1-month suspension group), and 9.8% (44 of 451 women in the 2-month suspension group). No subgroups were identified in which brief suspension of hormone therapy resulted in decreased mammography recall. With suspension, decreases in percentage of breast density were orderly and statistically significant: 0.1% (no-suspension group), âˆ’0.9% (1-month suspension group), and âˆ’1.5% (2-month suspension group). Similar ordered decreases were observed for dense area. Women in the suspension groups experienced increased menopause symptoms.
Results can only be generalized to women age 45 to 80 years who have used hormone therapy for at least 1 year and will consider short-term suspension; most eligible women (61%) declined participation. Mammography recall was determined by 1 expert radiologist.
Brief hormone therapy suspension was associated with small changes in breast density and did not affect recall rates. No evidence supports short-term hormone therapy suspension before mammography.
U.S. Department of Defense and the National Cancer Institute.
Rowan T Chlebowski
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
June 30, 2009
Hormone Therapy Suspension and Mammography in the Women's Health Initiative Clinical Trials
The Women's Health Initiative (WHI) randomized clinical trials evaluating hormonal therapy have previously published findings which address and expand those recently published by Buist and colleagues (1). In the WHI clinical trial evaluating estrogen plus progestin, 16,608 postmenopausal women were randomized to receive combined hormone therapy or placebo. When the trial intervention was ended, women were informed by letter to stop study pills that day and almost all did. Women in the combined estrogen plus progestin group had significantly more mammograms requiring a physician-directed intervention (short interval follow-up suggested, suspicious abnormalities, and those highly suggestive of malignancy) during the intervention (2) and throughout first post-intervention year but not thereafter (P=0.005) (3) Thus, somewhat over one year is required for improvement in mammography performance after stopping combined estrogen plus progestin use.
In an ancillary study in the same WHI clinical trial, the association between combined estrogen plus progestin use and mammographic density was examined in a randomly identified sub-sample of trial participants. In this randomized population of 1,413 postmenopausal women, there was a statistically significant 6.0% increase in density after 1 year and a 4.9% increase at 2 years with estrogen plus progestin use findings (4) The magnitude of the increase in breast density was somewhat higher than in the cited PEPI trial. Taken together, the PEPI and WHI findings suggest that changes in breast density associated with combined hormone therapy use are substantially greater in magnitude than those observed during a menstrual cycle.
Finally, in the WHI randomized clinical trial evaluating estrogen alone in postmenopausal women with prior hysterectomy which randomized 10,739 participants, mammograms suspicious or highly suggestive of malignancy were not increased in the estrogen alone hormone groups (5) a finding which was different from that reported in the WHI combined hormone therapy trial where an increase in abnormal mammograms was seen with estrogen plus progestin (2). Thus, differences in mammography recall rates between women receiving estrogen alone compared to combined estrogen plus progestin use would be anticipated. Awareness of these findings from the WHI randomized trials should put those of Buist and colleagues in a more complete clinical context.
1. Buist DSM, Anderson ML, Reed SD, et al. Short-term hormone therapy suspension and mammography recall. A randomized trial. Ann Intern Med 2009;150:752-765.
2. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative randomized trial. JAMA 2003;289:3243 -53.
3. Chlebowski RT, Anderson GL, Petinger M, et al. Estrogen plus progestin and breast cancer detection by means of mammography and breast biopsy. Arch Intern Med 2008;168:370-7.
4. McTiernan A, Martin C, Peck J, et al. Estrogen and progestin influence on mammogram density in healthy postmenopausal women in the Women's Health Initiative Randomized Trial. J Natl Cancer Inst. 97(8):684 -91, 2005.
5. Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography in postmenopausal women with hysterectomy: The Women's Health Initiative randomized trial JAMA 242:1048-63, 2006.
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