ORIGINAL CONTRIBUTION Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women The Women���s Health Initiative Randomized Trial Rowan T. Chlebowski, MD, PhD Susan L. Hendrix, DO Robert D. Langer, MD, MPH Marcia L. Stefanick, PhD Margery Gass, MD Dorothy Lane, MD, MPH Rebecca J. Rodabough, MS Mary Ann Gilligan, MD, MPH Michele G. Cyr, MD Cynthia A. Thomson, PhD, RD Janardan Khandekar, MD Helen Petrovitch, MD Anne McTiernan, MD, PhD for the WHI Investigators Bfully REAST CANCER IS THE MOST common invasive cancer in US women and its etiology is not defined.1,2 Despite obser- vational studies suggesting increased breast cancer risk with estrogen3 and especially long-duration combined hor- mone use,4,5 the magnitude of breast cancer risk associated with meno- pausal hormone therapy is controver- sial.6,7 On July 9, 2002, the Women���s Health Initiative (WHI) reported results from the randomized controlled trial of 16608 postmenopausal women com- paring effects of estrogen plus proges- tin with placebo on chronic disease risk and confirmed that combined estro- Author Affiliations: Harbor-UCLA Research and Edu- cation Institute, Torrance, Calif (Dr Chlebowski) Wayne State University, Detroit, Mich (Dr Hendrix) Univer- sity of California San Diego School of Medicine, La Jolla (Dr Langer) Department of Medicine, Stanford Uni- versity, Palo Alto, Calif (Dr Stefanick) Department of ObstetricsandGynecology,UniversityofCincinnatiCol- lege of Medicine, Cincinnati, Ohio (Dr Gass) Depart- ment of Preventive Medicine, State University of New York, Stony Brook (Dr Lane) Fred Hutchinson Cancer Research Center, Seattle, Wash (Ms Rodabough) De- partment of Medicine, Medical College of Wisconsin, Milwaukee(DrGilligan) DepartmentofMedicine,Brown Medical School, Providence, RI (Dr Cyr) University of Arizona, Tucson (Dr Thomson) Department of Medi- cine, Evanston Northwestern Healthcare, Evanston, Ill (Dr Khandekar) Department of Geriatrics and Medi- cine, John A. Burns School of Medicine, Honolulu, Ha- waii (Dr Petrovitch) and Fred Hutchinson Cancer Re- search Center, Seattle, Wash (Dr McTiernan). Corresponding Author and Reprints: Rowan T. Chlebowski, MD, PhD, Harbor-UCLA Research and Education Institute, 1124 W Carson St, Bldg J-3, Tor- rance, CA 90502 (e-mail: rchlebowski@rei.edu). Context The Women���s Health Initiative trial of combined estrogen plus progestin was stopped early when overall health risks, including invasive breast cancer, ex- ceeded benefits. Outstanding issues not previously addressed include characteristics of breast cancers observed among women using hormones and whether diagnosis may be influenced by hormone effects on mammography. Objective To determine the relationship among estrogen plus progestin use, breast cancer characteristics, and mammography recommendations. Design, Setting, and Participants Following a comprehensive breast cancer risk assessment, 16608 postmenopausal women aged 50 to 79 years with an intact uterus were randomly assigned to receive combined conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo from 1993 to 1998 at 40 clinical centers. Screening mammography and clinical breast examinations were per- formed at baseline and yearly thereafter. Main Outcome Measures Breast cancer number and characteristics, and fre- quency of abnormal mammograms by estrogen plus progestin exposure. Results In intent-to-treat analyses, estrogen plus progestin increased total (245 vs 185 cases hazard ratio [HR], 1.24 weighted P .001) and invasive (199 vs 150 cases HR, 1.24 weighted P=.003) breast cancers compared with placebo. The invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology and grade but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively P=.04) and were at more advanced stage (regional/metastatic 25.4% vs 16.0%, respec- tively P=.04) compared with those diagnosed in the placebo group. After 1 year, the percentage of women with abnormal mammograms was substantially greater in the estrogen plus progestin group (716 [9.4%] of 7656) compared with placebo group (398 [5.4%] of 7310 P .001), a pattern which continued for the study duration. Conclusions Relatively short-term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. These results suggest estrogen plus progestin may stimulate breast can- cer growth and hinder breast cancer diagnosis. JAMA. 2003 289:3243-3253 www.jama.com See also pp 3254 and 3304. ��2003 American Medical Association. All rights reserved. (Reprinted) JAMA, June 25, 2003���Vol 289, No. 24 3243 by guest on February 26, 2012 jama.ama-assn.org Downloaded from

gen plus progestin use increases the risk of invasive breast cancer.8 To better un- derstand the relationship between breast cancer and exposure to estro- gen plus progestin, a detailed analysis of the breast cancers that developed among women receiving active treat- ment compared with those receiving placebo was performed. METHODS Study Design The WHI combined estrogen plus pro- gestin randomized clinical trial en- rolled 16608 postmenopausal women with no prior hysterectomy from 1993 to 1998 at 40 clinical centers follow- ing a previously described design.8,9 The study was approved by human sub- jects committees at each institution. Women who were recruited by mass mailings and media were eligible if they were between 50 and 79 years of age at study entry, postmenopausal, and provided written informed consent. Women with prior hysterectomy, breast cancer, or those with medical condi- tions likely to result in death within 3 years were excluded. Prior meno- pausal hormone use required a 3-month wash out period before baseline test- ing. All women had baseline mammo- gram and clinical breast examina- tions abnormal findings required clearance before study entry. Women were randomly assigned to receive estrogen plus progestin taken as a single daily tablet containing con- jugated equine estrogens (0.625 mg) and medroxyprogesterone acetate (2.5 mg) (Prempro, Wyeth Ayerst, Phila- delphia, Pa) or to receive an identical- appearing placebo. Randomization by the WHI clinical coordinating center was implemented locally by using a dis- tributed study database and study medi- cation bottles with unique bar codes for blinded dispensing. Descriptive char- acteristics for the 2 groups were as- sessed at baseline (TABLE 1). Study medication was discontinued for development of breast cancer en- dometrial pathology (hyperplasia not responsive to treatment, atypia, or cancer) deep-vein thrombosis or pul- Table 1. Descriptive Characteristics of Participants at Baseline by Treatment Group* Characteristic No. (%) Estrogen + Progestin (n = 8506)��� Placebo (n = 8102) Age at screening, y 50-59 2839 (33.4) 2683 (33.1) 60-69 3853 (45.3) 3657 (45.1) 70-79 1814 (21.3) 1762 (21.7) Ethnicity White 7140 (83.9) 6805 (84.0) Black 549 (6.5) 575 (7.1) Hispanic 472 (5.5) 416 (5.1) American Indian 26 (0.3) 30 (0.4) Asian/Pacific Islander 194 (2.3) 169 (2.1) Unknown 125 (1.5) 107 (1.3) Education 0-8 y 202 (2.4) 177 (2.2) Some high school 373 (4.4) 362 (4.5) High school diploma/GED 1614 (19.1) 1608 (20.0) School after high school 3356 (39.7) 3059 (38.0) College degree or higher 2915 (34.5) 2838 (35.3) Gail Risk Assessment, % per 5 y 1.25 2806 (33.0) 2717 (33.5) 1.25-1.74 2859 (33.6) 2703 (33.4) 1.75 2841 (33.4) 2682 (33.1) Age at menarche, y 11 1725 (20.3) 1670 (20.7) 12-13 4578 (54.0) 4334 (53.7) 14 2182 (25.7) 2061 (25.6) No. of term pregnancies Never pregnant 655 (7.7) 633 (7.8) Never had term pregnancy 201 (2.4) 199 (2.5) 1 690 (8.2) 661 (8.2) 2 1908 (22.5) 1708 (21.2) 3 2020 (23.9) 1952 (24.2) 4 1416 (16.7) 1412 (17.5) 5 1575 (18.6) 1500 (18.6) Age at first birth, y Never pregnant/no term pregnancy 860 (11.2) 833 (11.5) 20 1124 (14.6) 1117 (15.4) 20-29 4996 (64.8) 4698 (64.6) 30 727 (9.4) 624 (8.6) No. of children breastfed None 3813 (45.3) 3669 (45.7) 1-2 2606 (31.0) 2485 (31.0) 3 2001 (23.8) 1867 (23.3) Oral contraceptive use, y No 4811 (56.6) 4655 (57.5) Yes 3693 (43.4) 3444 (42.5) 5 1982 (23.3) 1781 (22.0) 5 to 10 825 (9.7) 808 (10.0) 10 886 (10.4) 855 (10.6) Prior estrogen only use, y No 7603 (89.4) 7237 (89.3) Yes 903 (10.6) 864 (10.7) 5 677 (8.0) 659 (8.1) 5 to 10 134 (1.6) 109 (1.3) 10 92 (1.1) 96 (1.2) Prior estrogen plus progestin use, y No 6990 (82.2) 6706 (82.8) Yes 1516 (17.8) 1396 (17.2) 5 1050 (12.3) 997 (12.3) 5 to 10 315 (3.7) 258 (3.2) 10 151 (1.8) 141 (1.7) Recency of hormone use, y Nonuser 6277 (73.8) 6020 (74.3) Past 5 727 (8.6) 679 (8.4) Past 5 to 10 335 (3.9) 310 (3.8) Past 10 609 (7.2) 599 (7.4) Current 554 (6.5) 491 (6.1) (continued) ESTROGEN PLUS PROGESTIN AND BREAST CANCER 3244 JAMA, June 25, 2003���Vol 289, No. 24 (Reprinted) ��2003 American Medical Association. All rights reserved. by guest on February 26, 2012 jama.ama-assn.org Downloaded from