“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 We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence,” wrote the researchers.
The meta-analysis, published in The Lancet, included all relevant prospective studies found from Jan. 1, 1992, through Jan. 1, 2018, with data on type and timing of hormone therapy use.
Risks Based on Duration and Type of Hormone
At follow-up, 108,647 women (mean age [SD] 65  years) developed breast cancer, of whom just over half (51%, n = 55,575) had used hormone therapy. When complete patient data were available, among current users, mean duration of therapy was 10 years, compared to seven years in past users. Mean age was 50 years at menopause (SD 5) and at initiation of therapy (SD 6). With the exception of vaginal estrogens, all types of hormone therapy were associated with excess breast cancer risks. Risks increased with longer use. Use of estrogen-progestogen posed a greater risk than estrogen-only preparations. Current users still had an increased risk even during the first four years of therapy (estrogen-progestogen risk ratio (RR) 1.60, 95% confidence interval [CI] 1.52–1.69; estrogen-only RR 1.17; 95% CI 1.10–1.26), although the risk was substantially greater during years five through 14 (estrogen-progestogen RR 2.08, 95% CI 2.02–2.15; estrogen-only RR 1.33, 95% CI 1.28–1.37). During years five through 14, daily estrogen-progestogen use, compared to less frequent use, increased breast cancer risk (RR 2.30, 95% CI 2.21–2.40 vs. 1.93, 95% CI 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),” the researchers observed.
In some women, the risk continued even after ceasing therapy, in some cases for more than a decade. However, this was dependent on duration of use and excess risk was small in women who used hormone therapy for less than one year.
The authors summarized their findings by saying, “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).”
In a related editorial, Joanne Kotsopoulos, PhD, of the Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada, suggested that the findings be taken cautiously. For one, the review was limited to prospective studies, making it difficult to avoid bias. “Some women switch from being non-users to users in the follow-up and the duration of use is not a constant but changes each year that hormones are used,” she noted.
“Clinicians must heed the message of this study but also to take a rational and comprehensive approach to the management of menopausal symptoms, with careful consideration of the risks and benefits of initiating MHT for each woman,” Dr. Kotsopoulos recommended, adding, “For likely candidates, MHT (preferably oestrogen alone) should be initiated around the time of natural menopause and ideally limited to 5 years of use.”