Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial

Abstract

Background In contrast to many observational studies, women in the Women’s Health Initiative (WHI) trial randomised to oestrogen-alone had lower invasive breast cancer incidence than those assigned placebo. Influence of oestrogen use on breast cancer mortality has not been reported. Methods Between 1993 and 1998, the WHI enrolled 10,739 postmenopausal women from 40 US centres into a randomized, double-masked, placebo-controlled trial evaluating oral conjugated equine oestrogen (0·625 mg/d). Women aged 50–79 years with prior hysterectomy, anticipated 3-year survival, and mammography clearance were randomized by a computerized, permuted block algorithm, stratified by age group and centre, to receive oestrogen or matching placebo. The trial was terminated early, in 2004, for an adverse effect on stroke. In extended follow-up through August 2009, we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumor characteristics, and mortality. Cox regression models were used to estimate intention-to-treat hazard ratios [HRs]. Findings After a median 11.8 (interquartile range [IQR], 9·1 to 12·9) years of follow-up, conjugated equine oestrogen-alone use for a median of 5·9 (IQR, 2·5 to 7·3) years was associated with lower invasive breast cancer incidence compared to placebo (151 vs. 199 breast cancers; annualized rates, 0·27% vs. 0·35%; HR, 0·77; 95% confidence interval [CI], 0·62 to 0·95; P=0·02) with no difference (P=0·76) between intervention-phase (HR, 0·79; 95% CI, 0·61 to 1·02) and post-intervention effects (HR, 0·75; 95% CI: 0·51 to 1·09) ). Potential effect modification by benign breast disease (P=0·01) and family history of breast cancer (P=0·02) was observed. In the oestrogen-alone group fewer women died from breast cancer (6 vs.16 deaths; annualized rates 0·009% vs. 0·024%; HR, 0·37; 95% CI, 0·13 to 0·91; P=0.03) and fewer died from all causes after a breast cancer diagnosis (30 vs. 50 deaths; annualized rates, 0·046% vs. 0·076%; HR, 0·62; 95% CI, 0·39 to 0·9;, P=0·04). Interpretation Women with hysterectomy seeking relief of climacteric symptoms may be given reassurance regarding breast cancer influence of oestrogen use consistent with durations observed in this trial. However, these findings do not support oestrogen use for breast cancer risk reduction since this benefit may not apply to populations at higher risk. Funding US National Heart, Lung and Blood Institute. Wyeth provided study medications.

Celebrating 75 years of oestradiol

“…Several studies demonstrate objective tumor regressions, often prolonged, in women receiving exogenous oestrogen (Ellis et al 2009, Lonning 2009). This proapoptotic pathway may also explain why oestrogen used alone without a concomitant progestin in the Women's Health Initiative (WHI) study caused a paradoxical reduction in breast cancer in women lacking a uterus (Anderson et al 2012).…”

“…In this subset of women, there was no statistically significant increase in heart disease with ECP and a significant trend toward reduction in those using E alone. Quite surprising was the statistically significant reduction in the risk of breast cancer in the women receiving oestrogen alone (Anderson et al 2012;Fig. 11).…”

Progesterone signalling in breast cancer: a neglected hormone coming into the limelight

“…Women receiving HRT have little or no increase in breast cancer risk when taking oestrogens only, in fact there may even be a protective effect 19 . By contrast, a substantial increase in breast cancer risk was noticed in women taking combinations of an oestrogen and various synthetic progesterone agonists (progestins), despite this being standard of care in the United States and the United Kingdom [20][21][22] .…”

Proven value of translational research with appropriate animal models to advance breast cancer treatment and save lives: the tamoxifen tale

“…Recent data demonstrate that 10 years of tamoxifen is superior to 5 years of tamoxifen [81] but mortality is decreased by 50% compared with historical no treatment data but only in the decade after 10 years of tamoxifen is stopped. Oestrogen-induced apoptosis is also offered as the reason [82] mortality decreases with oestrogen alone treatment as hormone replacement therapy in 60 year old post-menopausal women following a decade of oestrogen deprivation following menopause. It may be that this research strategy leads to new and safer hormone replacement therapy for post-menopausal women.…”

“…This knowledge became pre-positioned in the refereed literature so that the paradoxical finding of fewer breast cancers reported in the oestrogen alone clinical trial of the WHI with a reduction of mortality were understood. Select women lived [82] but the finding that a combination of oestrogen plus a synthetic progestin, which causes an increase in breast cancer incidence, now demands understanding. Resolution of mechanisms and the creation of a safer hormone replacement therapy that prevents breast cancer may indeed be the next chapter of the tamoxifen tale that affects the lives of millions of women worldwide.…”