Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence

Abstract

Background: Published findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence.

Methods: Principal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users.

Findings: During prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1-4 (oestrogen-progestagen RR 1·60, 95% CI 1·52-1·69; oestrogen-only RR 1·17, 1·10-1·26), and were twice as great during years 5-14 (oestrogen-progestagen RR 2·08, 2·02-2·15; oestrogen-only RR 1·33, 1·28-1·37). The oestrogen-progestagen risks during years 5-14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21-2·40 vs 1·93, 1·84-2·01; heterogeneity p<0·0001). For a given preparation, the RRs during years 5-14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40-44, 45-49, 50-54, and 55-59 years, and were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese). After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following less than 1 year of MHT use.

Interpretation: If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50-69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.

Funding: Cancer Research UK and the Medical Research Council.

Figure 1

Estimated number of current MHT users in western countries in the 50 years since 1970, and the distribution of the dates of diagnosis of breast cancer in the retrospective and the prospective studies Vertical lines give median dates of diagnosis, and horizontal lines give IQRs. MHT=menopausal hormone therapy.

Figure 2

Type and timing of MHT use in current users and past users (A) All current and past users. (B) Past users only, by time since last use of MHT. Fully adjusted relative risks for current versus never users by years of current use, and for past users versus never users by years of use and time since cessation of use (prospective studies). MHT=menopausal hormone therapy.

Figure 3

Age at first use: relative risks during years 5–14 of current MHT use Fully adjusted relative risks for current versus never users during years 5–14 of current use, subdivided by age at first use of MHT, giving in each subgroup a mean age at menopause and mean duration of MHT use in cases (prospective studies). Tests for trend in RR with age of start of MHT use (χ², 1 degree of freedom): oestrogen-only MHT 4·04, p=0·044; oestrogen-progestagen MHT 6·44, p=0·011. MHT=menopausal hormone therapy.

Figure 4

Main types of MHT: relative risks during years 5–14 of current use Fully adjusted relative risks for current versus never users during years 5–14 (mean: year 9) of use. MHT=menopausal hormone therapy. Appendix p 45 gives results for uncommon constituents.

Figure 5

Tumour characteristics: relative risks during years 5–14 of current use Fully adjusted relative risks for current versus never users during years 5–14 (mean: year 9) of use. MHT=menopausal hormone therapy.

Figure 6

Relevance of BMI to the absolute 10 year breast cancer incidence rate per 100 women at ages 55–64 years in never users and in current users of MHT Adjusted relative risks for all cancers during 5–14 years of current use were calculated taking never users with a BMI of 25–29 kg/m² as the reference, and then standardising to the incidence rate of breast cancer in never users aged 55–64 years of average weight in western countries (ie, 3 per 100 women; appendix p 17). Separate results for ER+ and ER– breast cancer are shown (both with broken lines) only for never users of MHT (but are shown for current users in the appendix, p 48). BMI groups: <25 kg/m² (lean); 25–30 kg/m² (overweight); and ≥30 kg/m² (obese); incidence is plotted against mean BMI values. BMI=body-mass index. ER+=oestrogen-receptor positive. ER–=oestrogen-receptor negative. MHT=menopausal hormone therapy.

Figure 7

Effect of 5 years or of 10 years of MHT use, starting from age 50 years, on 20-year breast cancer incidence rates Relevance of MHT use and of adiposity to the absolute 20-year risk of developing breast cancer from ages 50–69 years inclusive, assuming that the relative risks found in the prospective studies would apply to women of average weight in a typical developed country in which the absolute 20-year risk of developing breast cancer in never users is 6·3 per 100 women (appendix pp 17, 18, 24, 25, 26). Results for women of average weight are shown for never users and for various categories of MHT use from age 50 years. A) Effects of 5 years or of 10 years of oestrogen-plus-daily-progestagen MHT. B) Effects of 5 years or of 10 years of oestrogen-plus-intermittent-progestagen MHT. C) Effects of 5 years or of 10 years of oestrogen-only MHT. D) Effects of adiposity among women who never use MHT, comparing those of average weight with those who were lean or obese. MHT=menopausal hormone therapy.