Menopausal hormone therapy is not suggested for menopausal symptoms after breast cancer.
The recommendation is weak because risk of breast cancer is probably increased and may be fatal. Values and preferences vary. Alternative treatments are not as effective for postmenopausal symptoms.
Comment: The quality of evidence is downgraded by inconsistency (variability in results across studies).
The HABITS trial 1 randomised 434 survivors of breast cancer (mean age 55 years, tumours up to stage II, free of recurrence) to receive either hormone replacement therapy (HRT) with cyclic or continuous oestrogen-progestagen combination or best symptomatic treatment without hormones. 345 women had at least one follow-up report at the time when the trial was stopped by the steering committee after a median follow-up of 2.1 years. The risk for recurrence of breast cancer among patients receiving menopausal hormone therapy was statistically significantly higher (26 vs 8, relative hazard [RH] = 3.3, 95% confidence interval [CI] = 1.5 to 7.4) than among those receiving no treatment. Eight serious adverse events were reported in the HRT group, four in the non-HRT group.
Another Swedish RCT, known as the Stockholm trial 2, was initiated concurrently with HABITS. Much of the design of both studies was similar, but a goal of the Stockholm protocol was to minimize the use of progestogen combined with estrogen. In this trial (378 patients), at a median follow-up of 4.1 years, the risk of breast cancer recurrence was not associated with menopausal hormone therapy (RH = 0.82, 95% CI = 0.35 to 1.9). Statistically significant heterogeneity in the rate of recurrence was observed (p=0.02) between the two studies, indicating that chance may not be the only explanation. Doses of estrogen and progestogen and treatment regimens for menopausal hormone therapy may be associated with the recurrence of breast cancer.
In 10 year follow up of the Stockholm randomised trial 3, there was no significant difference in new breast cancer events: 60 in the HRT group versus 48 among controls (hazard ratio 1.3; 95% CI 0.9 to 1.9). Among women on HRT, 11 had local recurrence and 12 distant metastases versus 15 and 12 for the controls. There were 14 contra-lateral breast cancers in the HRT group and 4 in the control group (HR 3.6; 95% CI 1.2 to 10.9; p=0.013). No differences in mortality or new primary malignancies were found. The increased recurrence in HABITS has been attributed to higher progestogen exposure.
A systematic review and meta-analysis 4 assessing the safety of menopausal hormone therapy in breast cancer survivors aged>50 years at diagnosis included 9 studies (four cohort, one case-control, four RCTs; n = 16 002). Very low quality evidence from observational studies demonstrated no adverse effect on tumour recurrence with HRT use (RR 0.80, 95% CI 0.53 to 1.19; I²=66%; n=11 984), while moderate quality evidence from RCTs demonstrated an adverse effect (RR 1.46, 95% CI 1.20 to 1.77; I²=17%; n=4108). Similarly, observational studies demonstrated no adverse effect on breast cancer-related mortality (RR 0.32, 95% CI 0.21 to 1.49; I²=0%, n=2182), while RCTs demonstrated a non-significant higher risk (RR 1.07, 95% CI 0.77 to 1.49; I²=0%; n=3918). Ultimately, despite conflicting findings, evidence of sufficient quality suggests that HRT may increase the risk of tumour recurrence in older survivors.
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