The HABITS trial was a randomized, open label trial on menopausal hormone therapy (MHT) that included breast cancer (BC) survivors (n=447, mean age 55 years, tumor stage ≤II) with bothersome vasomotor symptoms «Holmberg L, Anderson H, HABITS steering and data m...»1. Of BC survivors 56% randomized to MHT and 48% of controls had hormone receptor positive disease. Adjuvant treatment with tamoxifen was used by 21% of the participants. Node-positive disease was present in 26% of the women randomized to active treatment and in 21% of those on placebo. The participants were randomized to receive either MHT (mostly estradiol hemihydrate combined with cyclic or continuous norethisterone, chosen according to local practice) or best symptomatic hormone-free treatment. At a median follow-up of 2.1 years the risk of recurrent BC was higher in MHT users (relative hazard [RH] 3.5, 95% CI 1.5–7.4) compared with no hormonal treatment. The increased risk was seen in BC survivors with hormone receptor positive disease (relative hazard 4.8, 95%CI 1.1-21.4 [14 out of 159]), but not in those with hormone receptor negative BC (relative hazard 1.9, 95%CI 0.4-9.6 [6 out of 72]. In analyses with extended follow-up after stopping the trial, a total of 442 women could be followed for a median of 4 years «Holmberg L, Iversen OE, Rudenstam CM, ym. Increase...»2. In the MHT arm 39/221 women, and in the control arm 17/221 had a new BC (HR 2.4, 95% CI 1.3-4.2) with cumulative incidences at 5 years 22.2% and 8.0%, respectively. The effect of MHT on BC recurrence was different for hormone receptor positive (HR 2.6, 95%CI 1.3-5.4 [37 out of 268]) and negative (HR 1.8, 0.7-4.8 [19 out of 174]) diseases.
Comment: This trial was stopped early due to the increased risk in recurrent breast cancer in the MHT arm.
Compared to other trials on MHT in BC survivors, this study included a higher proportion of women with node-positive BC, and thus possible subclinical disease, also the percentage of adjuvant tamoxifen use was low. The most commonly used MHT in the HABITS trial was an androgenic progestin (norethisterone), which may have a different effect of the risk of recurrent BC than a non-androgenic progestin.
The Stockholm trial was a randomized open-label designed to minimize exposure to progestin used for endometrial protection in MHT «von Schoultz E, Rutqvist LE, Stockholm Breast Canc...»3. Women (n=378, mean age 57-88 years, with a history of early stage BC were randomized to MHT (n = 188) or no MHT (n = 190). Adjuvant treatment with tamoxifen was used by 52%. Node-positive disease was present in 16% of the women randomized to active treatment and in 20% of those on placebo. Cyclical MHT (2mg daily estradiol for 3 weeks, then complemented with 10mg medroxyprogesterone acetate (MPA) for the last 10 days, then 1 week pause in MHT) was given to younger than 55. For older women MHT consisted of daily estradiol 2 mg for 12 weeks, complemented with 20 mg of daily MPA for the last 2 weeks, followed by 1 week with no treatment. In contrast to the HABITS trial «Holmberg L, Anderson H, HABITS steering and data m...»1 not significant differ between MHT users and controls (HR 1.3, 95% CI 0.9-1.9), in the Stockholm trial, at a median follow-up of 4.1 years, the risk of recurrent BC associated with MHT use was not elevated (HR 0.82, 95% CI = 0.35–1.9) «von Schoultz E, Rutqvist LE, Stockholm Breast Canc...»3. Furthermore, after extended 10.8 years of follow-up the number of new BCs did although more cancers in the contralateral breast were found in MHT users (HR = 3.6; 95% CI = 1.2–10.9; p = 0.013) «Fahlén M, Fornander T, Johansson H, ym. Hormone re...»4. No increased mortality from breast cancer or other causes was associated with MHT use.
Comment: Compared with the HABITS trial that yielded different results, women in the Stockholm trial were more often users of tamoxifen, which could protect from BC recurrence. The progestin was also different in this trial. In 2002, a joint data monitoring committee for both the HABITS [R1] and the Stockholm [R2] concluded that pooled data form both trials indicated a significant risk of recurrence of BC from MHT, that caused both studies to be prematurely stopped in December 2003.
Clinical comment: The use of sequential progestin every three months may not be enough for endometrial protection.
The Liberate «Kenemans P, Bundred NJ, Foidart JM, ym. Safety and...»5 studied tibolone (MHT with both estrogenic, progestogenic and androgenic properties) compared with placebo on the risk of recurrent BC. A total of 3098 women (mean age 52.7 years, 73% on adjuvant treatment, 58% with node-positive disease) were randomized to receive either 2.5mg tibolone or daily placebo. After a mean use of study medication for 2.7 years and a median follow-up of 3.2 years, 15.2% of women on tibolone had recurrent BC compared with 10.7% of women on placebo (HR 1.40, 95% CI 1.14-1.70), but this was only seen in BCS with HR-positive disease (HR 1.56, 95%CI 1.22-2.01), whereas HR-negative disease conferred no statistically significant increased risk (HR 1.15, 95%CI 0.73-1.80). Users of AIs at baseline had a higher risk of recurrence than tamoxifen-users (HR 2.42, 95%CI 1.01-5.79 vs HR 1.25, 95%CI 0.98-1.59). No differences were noted between the treatment groups regarding mortality or the risk of other malignancies than BC, or cardiovascular events.
Comment: The study was closed 5 months in advance due to increased BC recurrence with tibolone. Women randomized to receive placebo had a lower (10.7%) than expected (15%) incidence of recurrent BC, but a higher percentage women of node-positive disease. Moreover, subgroup analyses were limited in number of participants.
A systematic review and meta-analysis «Coronado PJ, Gómez A, Iglesias E, ym. Eligibility ...»6 included 12 studies: 3 RCTs (2 on menopausal hormone therapy [MHT] with n=378 [Stockholm study] and n=442 [HABITS], and 1 on tibolone [LIBERATE], n=3148), and 3 prospective and 6 retrospective studies on MHT vs no use. Largest non-randomized study included 1913 BCS, and the smallest 123 BCS. The use of tamoxifen was allowed in all but one prospective study that included only women with hormone receptor -negative tumors. The percentage of unknown hormone receptor status in the studies varied between 0 and 75%. For two retrospective studies data on both tamoxifen use or HR-status was not available. Mean age of the included BC survivors varied between 49-60 years and median follow-up 2.1-10.8 years. The data were analyzed regarding recurrence of BC after MHT compared with no treatment or placebo. Overall, pooled analysis showed nonsignificant heterogeneity of the data in the RCTs, but for all pooled data the heterogeneity was greater and significant (I2 72%, p<0.001).
In this review, the combined analysis of the Stockholm and HABITS trials showed no statistically significant increased risk of BC recurrence at 4 years (RR 1.46, 95%CI 0.56-3.83), or after including the 10-year follow-up from the Stockholm trial (RR1.64, 95%CI 0.91-2.94). A combined analysis of all 3 RCTs showed an increased risk of a new BC (RR 1.48, 95%CI 1.16-1.88). The risk of recurrent BC was significantly lower compared with no treatment in the only study that included solely women with HR-negative disease and receiving conjugated estrogens, (RR 0.26, 95%CI 0.70-2.09).
A pooling of the data from the RCTs and prospective studies (excluding the study on only HR-negative disease) the recurrence risk did not differ between treated and non-treated women (RR 1.23, 95%CI 0.66-2.27). A pooled analysis on retrospective studies (RR 0.64, 95%CI 0.45-1.01), or studies with estrogen-only arms (RR 0.85, 95%CI 0.54-1.33) did not show a significant effect post-diagnosis MHT use on the risk of BC recurrence. Analyses across all types of studies and treatment modalities show no difference in mortality risk between MHT users and controls (RR 0.91, 95%CI 0.38-2.19), although data from the retrospective cohorts a significant reduction in BC-related mortality was seen (RR 0.34, 95% 0.22-0.54).
General comment: The quality of evidence is downgraded by inconsistency in results, and rather small numbers of cases. Thus, no definite answer is yet found to the question whether MHT increases the risk of BC recurrence, and whether there is a dose or formulation that could be deemed safer than other. The increase in recurrence risk with post-diagnosis MHT may be concentrated to women with hormone receptor positive disease.