Findings from the Collaborative Group on Hormonal Factors in Breast Cancer on type and timing of menopausal hormone therapy (MHT) and breast cancer risk coming from an individual participant meta-analysis of the worldwide epidemiological evidence show that in western countries among approximately 20 million breast cancers diagnosed since 1990, about 1 million is caused by MHT use. Women who started systemic hormone therapy around the time of menopause were at greater risk of invasive breast cancer than apparently similar never users. Excess risks were greater among current than past users, but some risk persisted for more than a decade after MHT use ceased. There was little excess risk after use of MHT for less than 1 year, but there were definite excess risks associated with just 1–4 years of use, and progressively greater risks with longer use.
For a given duration of use, the excess risk among current users of MHT was greater for oestrogen receptor (ER)-positive that for ER-negative disease. The risk was greater for oestrogen-progestagen than for oestrogen-only preparations, particularly if progestagen use was daily rather than intermittent. Risks did not differ substantially between the main oestrogenic constituents, or by whether oestrogens were administered orally or transdermally. There appeared to be little risk, however, from topical vaginal oestrogen preparations, which limit systemic exposure. For the oestrogen-progestagen preparations, risks did not generally differ between different progestagenic constituents, including micronised (natural) progesterone, but appeared to be somewhat lower for combinations containing dydrogesterone. The corresponding risks with 10 years of use starting at age 50 years would be about twice as great. The findings are published on 29 August 2019 in the Lancet.
The collaborative group explained in the study background that a previous meta-analysis of the worldwide evidence published in 1997 found that current and recent users of MHT were at an increased risk of breast cancer, but little information was available about the effects of different types of MHT, or about long-term risks after MHT use had ceased. Since then, much new information has become available, including results from randomised trials, generally showing greater risks of breast cancer with preparations containing both oestrogen and progestagen than with preparations containing oestrogen alone, but published information on long-term effects of past use has remained limited.
The MHT has been used mostly in western countries, with about 600 million woman-years of use since 1970. Use increased rapidly during the 1990s, halved abruptly in the early 2000s, and stabilised during the 2010s with about 12 million current users. Women tend to begin MHT at around the time of the menopause and can continue for several years. At these ages, breast cancer is the most common malignancy in western countries; almost 3% of women are diagnosed with it during their 50s. While regulatory bodies in Europe and the USA recommend that MHT be used for the shortest time that it is needed, some clinical guidelines recommended less restrictive prescribing.
In the current study, the authors bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence. 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 1992 to 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.
During prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years; 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years in current users and 7 years in past users, and mean age was 50 years at menopause and 50 years 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; oestrogen-only RR 1.17), and were twice as great during years 5–14 (oestrogen-progestagen RR 2.08; oestrogen-only RR 1.33). The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2.30 vs 1.93; heterogeneity p < 0.0001).
For a given preparation, the RRs during years 5–14 of current use were much greater for ER-positive tumours than for ER-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.
The authors concluded that 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.
Central data collection, checking, analysis, and manuscript preparation was supported by the core funding of the Cancer Epidemiology Unit by Cancer Research UK and the Medical Research Council.
Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet;Published online 29 August 2019. DOI: https://doi.org/10.1016/S0140-6736(19)31709-X