Over 20-year median follow-up after 2 placebo-controlled randomized clinical trials (RCT) from Women's Health Initiative (WHI) «Chlebowski RT, Anderson GL, Aragaki AK, ym. Associ...»1 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.
The trial involved 16 608 postmenopausal women with an 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 other arm involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The mean baseline age was 63.3 (7.1) years. In all, 33.4% were aged 50-59 years, 33.4% aged 60-69 and 21.3% aged 70-79 years at the start of the trial. The CEE-plus-MPA arm 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.
Among 27 347 postmenopausal women who were randomized in both trials, 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 an 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) but 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).
In this long-term follow-up study of 2 RCTs, 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 intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.
Comment: The MHT used was CEE or CEE+ MPA which are not used in Finland.
The Finnish registry based nationwide study «Mikkola TS, Savolainen-Peltonen H, Tuomikoski P, y...»2 included 489,105 women using menopausal hormone therapy (MHT). The observed deaths were compared with those in the age-standardized background population. They were followed from the MHT initiation (3.3 million cumulative exposure years) to breast cancer death (n = 1,578 women).
The study identified from the Finnish prescription register all women aged 40 years or older who had bought various systemic MHT regimens from January 1, 1994 to the end of 2009. In all, 489,105 women with the use of systemic estrogen therapy (ET) or estrogen-progesterone (EPT) were studied. In EPT regimens the principal progestin components were norethisterone acetate (43%), medroxyprogesterone acetate (30%), and dydrogesterone (12%). The doses of oral estradiol were 1 or 2 mg/d, and those of transdermal were 25 μg/d to 100 μg/d (patch) or 0.5 to 1.5 mg (gel) alone or combined with various progestogens in fixed commercial preparations. The EPT could be administered sequentially (10-14 d courses of progestin at 1-3 month intervals) or continuously (daily progestin). The authors did not differentiate between oral and transdermal routes, type of EPT, or various progestins. Women using only vaginal estradiol were excluded.
The mean ± SD exposure for any MHT was 6.8 ± 6.0 years, for ET 5.7 ± 5.4 years, and for EPT 6.1 ± 6.1 years. The mean age at the initiation of MHT was 52 years. From the MHT users, 1,578 (0.3%) died of breast cancer during the total follow-up of 5.4 million years.
The breast cancer mortality risk was reduced in all MHT users with exposure for at most 5 years (standardized mortality ratio 0.56; CI 0.52-0.60), more than 5 to 10 years (0.46; 0.41-0.51), or more than 10 years (0.62; 0.56-0.68). A significantly larger risk reduction was detected in the 50 to 59 years age group (0.33; 0.29-0.37) compared with 60 to 69 (0.64; 0.59-0.70) or 70 to 79 (0.78; 0.69-0.87) years age groups. The death risk reductions in ET users tended to be larger in all age groups compared with EPT users, with a significant difference only in the 70 to 79 years age group (0.66; 0.57-0.76 vs 0.88; 0.77-1.00). The age at MHT initiation, regardless whether ET or EPT, showed no association with breast cancer mortality.
In the Finnish unselected population, breast cancer is fatal in 1 of 10 patients. Current data imply that this risk is prevalent in 1 of 20 patients with history of MHT use.
Comment: Nation based observational registry study may have "healthy women" bias.