Analysis of data from the UK Million Women Study (MWS) indicates that the risk of breast cancer with hormone replacement therapy (HRT) increases if it is started sooner rather than later after menopause.

The MWS is a very large (about 1.3 million) cohort study in the UK, launched in 1997 with the primary purpose of examining the effect of HRT on women’s health. It has previously confirmed the association between HRT and increased risk of breast cancer, and the purpose of this analysis was to determine how risk varied according to type and timing of HRT use. Participants were recruited between May 1996 and December 2001, providing a wide range of baseline health and demographic data, and they were re-surveyed after three years. Follow-up is for cancer diagnosis and death via central NHS registers. This analysis was restricted to post-menopausal women with known HRT use status and no previous cancer history (except non-melanoma skin cancer). They were classed as past, current or never users of HRT and analysed according a range of variable including type of HRT used (oestrogen only or oestrogen plus progestogen) and interval between menopause and first use. Study outcome was diagnosis of breast cancer.

The analysis included 1,129,025 eligible women, whose average age at study entry was 56.6 years. At last contact, 55% were ever users of HRT and 35% were current users. Total follow up was 4.05 million woman-years of follow-up, and over this time there were 15,759 incident breast cancers: 9632 (61%) were in HRT ever users and 7107 (45%) in current users. The analysis confirmed the results of that previously published from MWS, with larger numbers: users had an increased risk of breast cancer – for current users the relative risk (RR) compared to never users was 1.68 (95% CI 1.64 to 1.72). Overall risk for past users was increased (RR 1.08; 95% CI, 1.04 to 1.12) however this was concentrated in the first few years after discontinuation: it was slightly raised at two years and had disappeared by four years from discontinuation.

Both oestrogen-only and combined HRT were associated with increased risk, as was tibolone. The increase in risk for oestrogen-only use was less than that for combined preparations (RR 1.38; 95% CI 1.32 to 1.44, vs. RR 1.96; 95% CI 1.90 to 2.02). Use at or shortly after menopause was associated with increased risk both for oestrogen-only and combined HRT. Among current users of oestrogen-only formulations, there was little or no increase in risk if use began 5 years or more after menopause (RR = 1.05, 95% CI 0.89 to 1.24), but risk was statistically significantly increased if use began before or less than 5 years after menopause (RR = 1.43, 95% CI 1.35 to 1.51). A similar pattern was observed among current users of combined formulations (RR = 1.53, 95% CI = 1.38 to 1.70, and RR = 2.04, 95% CI = 1.95 to 2.14, respectively).

The authors conclude that they found substantial heterogeneity in the risk of breast cancer among HRT users. Combined HRT was associated with greater risk than oestrogen-only, and starting at or close to the menopause with greater risk than later. They note differences between their study population and others, most notably that of the US Women’s Health Initiative.