Rowan T Chlebowski1, Garnet L Anderson2, Aaron K Aragaki2, JoAnn E Manson3, Marcia L Stefanick4, Kathy Pan1, Wendy Barrington5, Lewis H Kuller6, Michael S Simon7, Dorothy Lane8, Karen C Johnson9, Thomas E Rohan10, Margery L S Gass2, Jane A Cauley6, Electra D Paskett11, Maryam Sattari12, Ross L Prentice2. 1. Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California. 2. Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, Washington. 3. Division of Public Health Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 4. Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, California. 5. Department of Epidemiology, University of Washington, Seattle, Washington. 6. Department of Epidemiology, School of Public Health, University of Pittsburgh, Pennsylvania. 7. Department of Oncology, Karmanos Cancer Institute at Wayne State University, Detroit, Michigan. 8. Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, New York. 9. Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis. 10. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York. 11. College of Public Health, The Ohio State University, Columbus. 12. Division of General Internal Medicine, University of Florida Health Internal Medicine, Gainesville.
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.
RCT Entities:
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 cancermortality 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 cancermortality, 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.
Authors: Judith K Ockene; David H Barad; Barbara B Cochrane; Joseph C Larson; Margery Gass; Sylvia Wassertheil-Smoller; JoAnn E Manson; Vanessa M Barnabei; Dorothy S Lane; Robert G Brzyski; Milagros C Rosal; Judy Wylie-Rosett; Jennifer Hays Journal: JAMA Date: 2005-07-13 Impact factor: 56.272
Authors: Jacques E Rossouw; Garnet L Anderson; Ross L Prentice; Andrea Z LaCroix; Charles Kooperberg; Marcia L Stefanick; Rebecca D Jackson; Shirley A A Beresford; Barbara V Howard; Karen C Johnson; Jane Morley Kotchen; Judith Ockene Journal: JAMA Date: 2002-07-17 Impact factor: 56.272
Authors: JoAnn E Manson; Rowan T Chlebowski; Marcia L Stefanick; Aaron K Aragaki; Jacques E Rossouw; Ross L Prentice; Garnet Anderson; Barbara V Howard; Cynthia A Thomson; Andrea Z LaCroix; Jean Wactawski-Wende; Rebecca D Jackson; Marian Limacher; Karen L Margolis; Sylvia Wassertheil-Smoller; Shirley A Beresford; Jane A Cauley; Charles B Eaton; Margery Gass; Judith Hsia; Karen C Johnson; Charles Kooperberg; Lewis H Kuller; Cora E Lewis; Simin Liu; Lisa W Martin; Judith K Ockene; Mary Jo O'Sullivan; Lynda H Powell; Michael S Simon; Linda Van Horn; Mara Z Vitolins; Robert B Wallace Journal: JAMA Date: 2013-10-02 Impact factor: 56.272
Authors: David J Cote; John L Kilgallon; Noah L A Nawabi; Hassan Y Dawood; Timothy R Smith; Ursula B Kaiser; Edward R Laws; JoAnn E Manson; Meir J Stampfer Journal: J Clin Endocrinol Metab Date: 2022-03-24 Impact factor: 5.958