Two nested case-control studies 5 from 2 databases in UK assessing the risks of breast cancer associated with different types and durations of menopausal hormone therapy (HT) included 98 611 women aged 50-79 with a primary diagnosis of breast cancer in 1998-2018, matched to 457 498 female controls. Overall, 34% women with a diagnosis of breast cancer and 31% controls had used HT prior to one year before the index date. Compared with never use, in recent users (<5 years) with long term use (HASH(0x2ed2410)5 years), oestrogen only therapy and combined oestrogen and progestogen therapy were both associated with increased risks of breast cancer (adjusted odds ratio 1.15, 95% CI 1.09 to 1.21 and 1.79, 95% CI 1.73 to 1.85, respectively). For combined progestogens, the increased risk was highest for norethisterone (1.88, 1.79 to 1.99) and lowest for dydrogesterone (1.24, 1.03 to 1.48). Past long term use of oestrogen only therapy and past short term (<5 years) use of oestrogen-progestogen were not associated with increased risk. The risk associated with past long term oestrogen-progestogen use, however, remained increased (1.16, 1.11 to 1.21). In recent oestrogen only users, between 3 (in younger women) and 8 (in older women) extra cases per 10 000 women years would be expected, and in oestrogen-progestogen users between 9 and 36 extra cases per 10 000 women years. For past oestrogen-progestogen users, the results would suggest between 2 and 8 extra cases per 10 000 women years.
A meta-analysis 3 used individual participant data from all eligible prospective studies about the type and timing of HT. Every HT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use. Among current users, these excess risks were definite even during years 1-4 (oestrogen-progestagen RR 1.60, 95% CI 1.52 to 1.69; oestrogen-only RR 1.17, 1.10 to 1.26), and were twice as great during years 5-14 (oestrogen-progestagen RR 2.08, 2.02 to 2.15; oestrogen-only RR 1.33, 1.28 to 1.37). The oestrogen-progestagen risks during years 5-14 were greater with daily than with less frequent progestagen use (RR 2.30, 2.21 to 2.40 vs 1.93, 1.84 to 2.01; heterogeneity p<0.0001).
A Swedish prospective nationwide cohort study 4 included all women who received HASH(0x2ed2410)1 HT prescription during the study period 2005-2012 (290 186 ever-users), group-level matched (1 : 3) to 870 165 never-users; respectively, 6376 (2.2%) and 18 754 (2.2%) developed breast cancer. Current use of oestrogen-only therapy was associated with a slight excess breast cancer risk [odds ratio (OR) 1.08 (1.02 to 1.14)] and oestrogen plus progestogen therapy was higher [OR = 1.77 (1.69 to 1.85)] and increased with higher age at initiation. The OR for current use was 1.12 (1.04 to 1.20) for estradiol, 0.76 (0.69 to 0.84) for estriol, 4.47 (2.67 to 7.48) for conjugated oestrogens, and 1.68 (1.51 to 1.87) for tibolone. Oral and transdermal HT showed similar associations.
A Finnish register study 6 estimated the risk for breast cancer in women using postmenopausal estradiol-progestogen therapy in 1994-2005 (n=221 551). The standardized incidence ratio for all types of breast cancer was not elevated within the first 3 years of use, but it rose to 1.31 (95% CI 1.20 to 1.42) for the use from 3-5 years and to 2.07 (1.84 to 2.30) with 10 or more years of use. Exposure to sequential progestogen for 5 years or more was accompanied with a lower risk elevation (1.78, 1.64 to 1.90) than exposure to continuous use (2.44, 2.17 to 2.72). Oral and transdermal use of E2-progestogen therapy was associated with comparable risk elevations for breast cancer. The use of norethisterone acetate was accompanied with a higher risk after 5 years of use (2.03, 1.88 to 2.18) than that of medroxyprogesterone acetate (1.64, 1.49 to 1.79). The risk of lobular breast cancer increased sooner than that for ductal cancer and was detectable for E2-progestogen therapy use less than 3 years (1.35, 1.18 to 1.53). There was no excess risk of breast cancer with distant metastases among E2-progestogen therapy users.
Comment: The quality of evidence is upgraded by time-response gradient.
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