Evidence regarding the possible role of estrogen with or without progesterone on the incidence of breast cancer (BC) has been contradictory, with some studies demonstrating increased risk of disease and others showing a protective effect. In an attempt to further clarify treatment strategies, the Women’s Health Initiative (WHI), a longitudinal national women’s health study initiated in the 1990s and funded by the National Heart, Lung, and Blood Institute, followed women who were taking these medications prospectively to determine the incidence of new cases of BC. Although the WHI concluded in 2005, extension studies are continuing through 2027. 

Recently, longer-term data were published of two WHI trials conducted between 1993 and 1998 with follow-up through December 31, 2017, examining the association of BC incidence and mortality in women with an intact uterus who received prior estrogen plus progesterone or the use of prior estrogen only in women who had undergo a hysterectomy. 

Study participants included 27,347 postmenopausal women aged 50 to 79 years from 40 centers throughout the U.S. with no prior history of BC and a negative baseline screening mammogram who had undergo more than 20 years of median cumulative follow-up. The baseline mean age of these women was 63.4 years. 

In the trial of postmenopausal women with an intact uterus, of the 16,608 participants, 8,506 women were randomized to receive 0.625 mg/day of conjugated equine estrogen (CEE) plus 2.5 mg/day of medroxyprogesterone acetate (MPA) and 8,102 received placebo. In the trial of postmenopausal women who had undergo a hysterectomy, of the 10,739 study subjects, 5,310 received CEE alone and 5,429 received placebo. 

Both trials were terminated prematurely—the former after a median of 5.6 years and the latter after a median of 7.2 years—when results of earlier WHI studies reported on an increased risk of stroke, no effect on coronary heart disease incidence, and risks exceeding any potential benefit in postmenopausal women who had received estrogen +/- progesterone for primary disease prevention. 

It is worth noting that as a result of findings from the earlier stages of these WHI trials, in January 2003 the FDA issued a black box warning about the increased risk of myocardial infarction, stroke, thromboembolic events, and breast cancer in postmenopausal women who used products containing estrogen or estrogen and progestin. 

In this latest work from the WHI, the primary outcome of both WHI trials was BC incidence, whereas the secondary outcomes were deaths from BC and deaths after BC. 

Investigators of these trials found dichotomous results. The time between hormone therapy and the incidence of BC was estimated by cumulative HR plots. Postmenopausal women with an intact uterus receiving both CCE and MPA had a statistically significant higher BC incidence (HR 1.28; P <.001) with an annualized BC rate of 0.45% in hormone users compared with 0.36% in the placebo group but no increase in BC deaths (HR 1.35; P = 0.11). BC incidence increased from year 6 onward following CEE + MPA exposure. 

When BC was present, women on CCE + MPA tended to be diagnosed at a later stage and were more likely to have lymph node involvement. On the other hand, postmenopausal women who had undergone a hysterectomy and had received CEE only had a lower BC incidence (HR 0.78; P = .005) with an annualized BC rate of 0.30% in hormone users compared with 0.37% in the placebo group. This group had more patients who were Black, obese, had had prior hormone therapy exposure and had undergone a bilateral oophorectomy. 

The lowest BC risk was seen among those who did not have a first-degree relative with the disease and those who had not previously undergo a breast biopsy. Benefit was seen after 5 years of CEE-only use. When BC occurred, there was a strong association with CEE only use and ERBB2 (formerly HER2) negative cancers and lymph node–negative BC. This group also had a statistically significantly lower BC mortality rate (HR 0.6; P = .04) with an annualized mortality rate of 0.031% in hormone users versus 0.046% in the controls. 

The authors concluded that in postmenopausal women with an intact uterus who had received CCE and MPA, BC incidence was higher, but mortality was not increased. In postmenopausal hysterectomized women, a beneficial effect of CCE was seen both on BC incidence and BC deaths. This benefit would translate into two fewer deaths from BC and two fewer deaths after BC for every 10,000 person years of women following prior use of CEE alone.  Nonetheless, experts are still not advocating for the use of CEE for BC prevention due to its other unfavorable adverse effects, such as increased stroke risk and due to limitations of the study such as poor adherence to treatment regimens and difficulty in establishing causality based on past exposure. 

Pharmacists should be aware of the latest findings from this landmark study as it has shaped the course of women’s health.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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