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

Abstract

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 PARTICIPANTSLong-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. INTERVENTIONSIn 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 MEASURESThe 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 RELEVANCEIn 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 i...

Clinical practice guidelines on menopause: *An executive summary and recommendations: Indian menopause society 2019–2020

“…Indian data are sparse on the use of MHT; hence, this section is based on the guidelines developed by various societies. [ 8 147 148 149 150 151 ]…”

“…259. In the WHI trial, 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[ 151 ]…”

Long-Term Evaluation of Women Referred to a Breast Cancer Family History Clinic (Manchester UK 1987–2020)

“…However, whilst reduction of risk is of benefit, none of the trials to date have shown a survival benefit. This has led to the suggestion that premarin should be used for women at least 5 years post-menopausal and without a uterus, since in this group the Women’s Health Initiative trial use was associated with a survival advantage [ 79 ].…”

Reply to The Women's Health Initiative; hormone replacement therapy; and Surveillance, Epidemiology, and End Results data and The importance of comprehensive data and statistical testing in the interpretation of breast cancer incidence trends

“…In contrast to another assertion made by DeSantis and Siegel, there is information regarding longer‐term breast cancer risk among women in a combined HT trial who infrequently used systemic hormones after the intervention. In that study, a median of 5.6 years of CEE + MPA use sustained a statistically significant increase in breast cancer incidence through a median cumulative follow‐up of 13 years initially 3 and now 20 years 10 . On a population level, as combined HT use continues to occur at a low level, many women now entering menopause no longer experience the long‐term increase in the risk of breast cancer observed with combined HT use.…”