Association of Menopausal Hormone Therapy with Breast Cancer Incidence and Mortality during Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials

Rowan T. Chlebowski, Garnet L. Anderson, Aaron K. Aragaki, Jo Ann E. Manson, Marcia L. Stefanick, Kathy Pan, Wendy Barrington, Lewis H. Kuller, Michael S. Simon, Dorothy Lane, Karen C. Johnson, Thomas E. Rohan, Margery L.S. Gass, Jane A. Cauley, Electra D. Paskett, Maryam Sattari, Ross L. Prentice

Research output: Contribution to journalComment/debatepeer-review

Abstract

Hormone therapy (HT) for menopausal symptoms and its risk-to-benefit ratio have been a controversial topic within the scientific community for several decades. The complicated benefits and potential adverse events associated with menopausal HTwere first reported in 2002 by theWomen's Health Initiative (WHI). The WHI data showing that use of estrogen therapy was associated with an increased risk of endometrial hyperplasia and cancer led to loss of popularity of hormonal therapy. However, use and popularity of this therapy subsequently rose again following the discovery that adding progesterone to estrogen therapy minimized the associated risks. At present, the influence of menopausal HTon breast cancer risk is still undetermined, largely because results from observational studies and randomized clinical trials have been conflicting and inconsistent.Moreover, because earlier reports were based on short-term data, it is not known whether these trends persist over time and translate into an impact on the risk of death from breast cancer. The aim of this study was to report long-term updated findings for breast cancer incidence and breast cancer mortality over 20 years of follow-up of prior randomized trials that evaluated conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) in postmenopausal women with an intact uterus and CEE alone in postmenopausal women with prior hysterectomy. The study was conducted at 40 US centers. Participants were enrolled from 1993 to 1998 with follow-up through December 31, 2017. Long-term follow-up data were provided for 2 placebo-controlled randomized clinical trials involving 27,347 postmenopausal women aged 50 to 79 years with no prior breast cancer and negative baseline screeningmammogram. One trial involving 16,608 women with a uterus were split into 2 cohorts: 8506 were randomized to receive 0.625 mg/d of CEE plus 2.5 m/g of MPA and 8102 to a placebo. The second trial involved 10,739 women with prior hysterectomy who were randomized: 5310 to 0.625 mg/d of CEE alone and 5429 to a placebo. Both trials were stopped early aftermedian intervention periods of 5.6 years in the CEE-plus-MPA trial and 7.2 years in the CEE-alone trial. The primary study outcome was incidence of breast cancer; secondary outcomes were rates of deaths from breast cancer and mortality rates after breast cancer. A total of 27,347 postmenopausal women were randomized in both HT trials; among these, baseline mean age was 63.4 (SD, 7.2) years, and mortality information was available for more than 98% (after >20 years of median cumulative follow-up). Compared with placebo, use of CEE alone in 10,739 women with a prior hysterectomy was associated with significantly lower incidence of breast cancer with 238 cases (annualized rate, 0.30%) versus 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.65 0.93; P = 0.005) and was associated with significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) versus 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37 0.97; P = 0.04). Use of CEE plus MPA, compared with placebo, among 16,608 women with a uterus was associated with significantly higher incidence of breast cancer (584 cases [annualized rate, 0.45%] vs 447 cases [annualized rate, 0.36%]; HR, 1.28; 95% CI, 1.13 1.45; P < 0.001); unlike CEE alone, there was no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) versus 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94 1.95; P = 0.11). This long-term follow-up study of 2 randomized trials showed that prior randomized use of CEE alone, relative to placebo, was significantly associated with lower breast cancer incidence as well as breast cancer mortality among women who had a previous hysterectomy, whereas prior randomized use of CEE plus MPA, relative to placebo, was significantly associated with a higher breast cancer incidence among women who had an intact uterus but no significant difference in breast cancer mortality. Taken together, these findings suggest reexamination of current breast cancer risk reduction strategies.

Original languageEnglish (US)
Pages (from-to)737-739
Number of pages3
JournalObstetrical and Gynecological Survey
Volume75
Issue number12
DOIs
StatePublished - Dec 2020

ASJC Scopus subject areas

  • Obstetrics and Gynecology

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