Menopausal hormone therapy linked to breast cancer risk

An individual patient-level meta-analysis found that risk for breast cancer increased steadily with duration of use for all types of menopausal hormone therapy except vaginal estrogen and that risk was higher with estrogen-progestogen than estrogen-only formulations.


Hormone replacement therapy during menopause, in most forms and durations, is associated with increased risk for breast cancer, a recent study found.

Researchers performed an individual patient-level meta-analysis of data from prospective studies that included information on type and timing of hormone therapy use during menopause. Data were included from studies published from Jan. 1, 1992, to Jan. 1, 2018. Adjusted risk ratios (RRs) were calculated to compare groups of patients who used hormone replacement therapy and those who never did. The study results were published Aug. 29 by The Lancet.

Overall, 108,647 postmenopausal study participants developed breast cancer during prospective follow-up, and of these, 55,575 (51%) had used hormone therapy. Among women for whom information on type and timing of therapy was complete, mean treatment duration was 10 years in those currently using the drugs and 7 years in past users. Their mean age was 50 years at menopause and 50 years at initiation of menopausal hormone therapy. The researchers found that every type of menopausal hormone therapy, with the exception of vaginal estrogen, was associated with increased risk for breast cancer. This risk increased steadily with duration of use and was higher for estrogen-progestogen therapies than for estrogen-only therapies.

Patients currently taking hormone therapy were found to have increased risk during years 1 to 4 (RRs, 1.60 [95% CI, 1.52 to 1.69] for estrogen-progestogen therapy and 1.17 [95% CI, 1.10 to 1.26] for estrogen-only therapy), which increased during years 5 to 14 (RRs, 2.08 [95% CI, 2.02 to 2.15] and 1.33 [95% CI, 1.28 to 1.37], respectively). During years 5 to 14, those who took estrogen-progestogen were at higher risk with daily versus less frequent progestogen use. Excess risk for breast cancer persisted after menopausal hormone therapy was stopped for more than 10 years, with magnitude depending on duration of previous use.

The authors noted that longer follow-up is needed in women who have stopped prolonged hormone treatment, among other study limitations, but concluded that a higher risk for breast cancer is associated with almost all types of menopausal hormone therapy. If the associations prove to be causal, they wrote, five years of such therapy in average-weight women beginning at age 50 years would increase risk for breast cancer at ages 50 to 69 years by approximately 1 in every 50 users of estrogen plus daily progestogen, 1 in every 70 users of estrogen plus intermediate progestogen, and 1 in every 200 users of estrogen only.

Another recent study on hormone therapy looked at whether outcomes of estrogen therapy differ in women with and without bilateral salpingo-oophorectomy (BSO). The subgroup analysis of the Women's Health Initiative Estrogen-Alone Trial involved 40 clinical centers in the U.S. and 9,939 women 50 to 79 years of age who had had a hysterectomy and whose oophorectomy status was known. Patients were randomly assigned to receive conjugated equine estrogen, 0.625 mg/d, or placebo for a median duration of 7.2 years. The primary outcomes were incidence of coronary heart disease (CHD) and invasive breast cancer, all-cause mortality, and a global index composed of the previous end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture, assessed during the intervention phase and at 18-year cumulative follow-up. The results were published Sept. 10 by Annals of Internal Medicine.

Overall, 5,310 women assigned to estrogen therapy and 5,429 assigned to placebo were included in the analysis. No significant difference was seen in the effects of estrogen therapy according to BSO status, but age appeared to modify the effect of estrogen therapy in women who had previous BSO. During the intervention phase, estrogen therapy was significantly associated with adverse effects in women ages 70 years and older (hazard ratio for the global index, 1.42; 95% CI, 1.09 to 1.86). However, risk for the global index did not appear to be elevated in younger women. Women ages 50 to 59 years of age with BSO had a reduction in all-cause mortality with estrogen treatment during cumulative follow-up (hazard ratio, 0.68; 95% CI, 0.48 to 0.96), but older women with BSO did not. In women with conserved ovaries, regardless of age, estrogen therapy and outcomes did not appear to be associated.

The authors noted that the effects of estrogen therapy started immediately after BSO could not be rigorously examined, that only one type of estrogen therapy was studied, and that nonadherence to treatment may have affected their results, among other limitations. They concluded that a median of 7.2 years of menopausal estrogen-only therapy was associated with long-term reduced mortality and was relatively safe when started before age 60 years in women who had had a BSO. The authors also concluded that such therapy was not significantly associated with death or other major outcomes in women without BSO and that older age in women with BSO was associated with more adverse treatment effects of estrogen.