Where Are We 10 Years After the Women's Health Initiative?

Abstract

"The media attention surrounding the publication of the initial results of WHI in 2002 led to fear and confusion regarding the use of hormonal therapy (HT) after menopause. This led to a dramatic reduction in prescriptions for HT in the United States and around the world. Although in 2002 it was stated that the results pertained to all women receiving HT, subsequent studies from the Women's Health Initiative (WHI) and others clearly showed that younger women and those close to menopause had a very beneficial risk-to-benefit ratio. Indeed, the results showed similar protective effects for coronary disease and a reduction in mortality that had been shown in earlier observational studies, which had also focused on younger symptomatic women. In younger women, the increased number of cases of venous thrombosis and ischemic stroke was low, rendering them “rare” events using World Health Organization nomenclature. Breast cancer rates were also low and were found to be decreased with estrogen alone. In women receiving estrogen and progestogen for the first time in the WHI, breast cancer rates did not increase significantly for 7 years. Other data suggest that other regimens and the use of other progestogens may also be safer. It has been argued that in the 10 years since WHI, many women have been denied HT, including those with severe symptoms, and that this has significantly disadvantaged a generation of women. Some reports have also suggested an increased rate of osteoporotic fractures since the WHI. Therefore, the question is posed as to whether we have now come full circle in our understanding of the use of HT in younger women. Although it is appropriate to treat women with symptoms at the onset of menopause, because there is no proven therapy for primary prevention, in some women the use of HT for this role may at least be entertained."

The Lancet Oncology: 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

The Lancet Oncology, Early Online Publication,  

7 March 2012

doi:10.1016/S1470-2045(12)70075-XCite or Link Using DOI

 Feature

The Women's Health Initiative

Women who use the oestrogen-only form of hormone replacement therapy (HRT) appear less likely to develop breast cancer in the longer term, according to new research published in The Lancet Oncology. A follow-up study of over 7500 women from the Women's Health Initiative trial who took oestrogen for about 6 years and then stopped has found that they are over 20% less likely to develop breast cancer and remain significantly less likely to die from the disease than those who never used HRT, a period of nearly 5 years after stopping treatment. The findings are discussed further in a Comment.

 Summary

Background

By contrast with many observational studies, women in the Women's Health Initiative (WHI) trial who were randomly allocated to receive oestrogen alone had a lower incidence of invasive breast cancer than did those who received placebo. We aimed to assess the influence of oestrogen use on longer term breast cancer incidence and mortality in extended follow-up of this cohort.

Methods

Between 1993 and 1998, the WHI enrolled 10 739  postmenopausal women from 40 US clinical centres into a randomised, double-masked, placebo-controlled trial. Women aged 50—79 years who had undergone hysterectomy and had expected 3-year survival and mammography clearance were randomly allocated by a computerised, permuted block algorithm, stratified by age group and centre, to receive oral conjugated equine oestrogen (0·625 mg per day; n=5310) or matched placebo (n=5429). The trial intervention was terminated early on Feb 29, 2004, because of an adverse effect on stroke. Follow-up continued until planned termination (March 31, 2005). Consent was sought for extended surveillance from the 9786 living participants in active follow-up, of whom 7645 agreed. Using data from this extended follow-up (to Aug 14, 2009), we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumour characteristics, and mortality. We used Cox regression models to estimate hazard ratios (HRs) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00000611.

Findings

After a median follow-up of 11·8 years (IQR 9·1—12·9), the use of oestrogen for a median of 5·9 years (2·5—7·3) was associated with lower incidence of invasive breast cancer (151 cases, 0·27% per year) compared with placebo (199 cases, 0·35% per year; HR 0·77, 95% CI 0·62—0·95; p=0·02) with no difference (p=0·76) between intervention phase (0·79, 0·61—1·02) and post-intervention phase effects (0·75, 0·51—1·09).

In subgroup analyses, we noted breast cancer risk reduction with oestrogen use was concentrated in women without benign breast disease (p=0·01) or a family history of breast cancer (p=0·02). In the oestrogen group, fewer women died from breast cancer (six deaths, 0·009% per year) compared with controls (16 deaths, 0·024% per year; HR 0·37, 95% CI 0·13—0·91; p=0·03). Fewer women in the oestrogen group died from any cause after a breast cancer diagnosis (30 deaths, 0·046% per year) than did controls (50 deaths, 0·076%; HR 0·62, 95% CI 0·39—0·97; p=0·04).

Interpretation

Our findings provide reassurance for women with hysterectomy seeking relief of climacteric symptoms in terms of the effects of oestrogen use for about 5 years on breast cancer incidence and mortality. However, our data do not support use of oestrogen for breast cancer risk reduction because any noted benefit probably does not apply to populations at increased risk of such cancer.

Caveats and Concerns With New Study on Hormone Therapy and Breast Cancer

Note: references studies - WHI (Women's Health Initiative) and California Teachers Study

Clinicians vary in their approaches to HT, said Dr. Ursin. "Certain gynecologists are very careful with finding the right dose for each woman, and some even prescribe [estrogen] alone for women who have a uterus, but then monitor the uterus carefully. Please keep in mind that the risk of breast cancer associated with EPT is relatively moderate. The risk of endometrial cancer with [estrogen] alone is much higher — a more than 4-fold increase in risk in this same population of California teachers," she said.