Type and Timing of Menopausal Hormone Therapy May Affect Breast Cancer Risk

Use of menopausal hormonal therapy for 5 years around the start of menopause may be associated with increased risk for breast cancer.

Use of menopausal hormonal therapy (MHT) for 5 years starting at age 50 may be associated with increased risk for breast cancer at ages 50 to 69 years, according to study results published in The Lancet.1 Approximately half the excess risk is concentrated in the first 5 years of MHT, with the remaining half spread over the next 15 years.

There are inconsistent findings and limited long-term data regarding the associations of different types of MHT and the risk for breast cancer. In this meta-analysis, researchers reviewed evidence from epidemiologic and randomized studies on these associations.

Information was obtained from 58 studies conducted between January 1992 and January 2018 that included data from 143,887 postmenopausal women with invasive breast cancer and 424,972 without breast cancer. A total of 24 prospective studies contributed data from 108,647 women; 55,575 of these (51%) had used MHT. The other 34 retrospective studies contributed data from 35,240 women, of whom 15,642 (44%) had used MHT.

In current MHT users, there was significant excess risk even during years 1 to 4 of current MHT use: the relative risk (RR) for estrogen-progestogen formulations was 1.60 (95% CI, 1.52-1.69) and for estrogen-only MHT it was 1.17 (95% CI, 1.10-1.26). During years 5 to 14 of use, current MHT use was associated with RRs of 2.08 (95% CI, 2.02-2.15) and 1.33 (95% CI, 1.28-1.37) for estrogen-progestogen and estrogen-only MHT, respectively.

Throughout years 5 to 14 of use of an estrogen-progestogen MHT, the RR was greater for a combination of estrogen with daily progestogen (RR, 2.30; 95% CI, 2.21-2.40) compared with estrogen with intermittent progestogen (RR, 1.93; 95% CI, 1.84-2.01).

For women who started MHT in the age groups of 40 to 44, 45 to 49, 50 to 54, and 55 to 59 years, RRs for breast cancer were similar. MHT was not frequently started at age 60 to 69 years. For this group, the excess risk during years 5 to 14 of current use was attenuated and significant only for combination of estrogen-progestogen MHT (RR, 1.75; 95% CI, 1.48-2.06), but not for estrogen-only MHT.

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Adiposity also attenuated the risk for breast cancer associated with MHT, particularly for estrogen-only MHT, suggesting that the use of an exogenous estrogen adds relatively little to the adiposity-associated estrogenic stimulation of breast tissue in women with obesity.

After MHT use ceased, some excess risk for breast cancer persisted for more than a decade. There was little added risk after <1 year of use, but there was definite excess risk associated with 1 to 4 years of use and increasingly higher risk with longer use.

The absolute risk for breast cancer occurring during the age range of 50 to 69 years was 6.3% in women of average weight who never used MHT. Use of combination estrogen-progestogen MHT for 5 years with 15 years of past use was associated with a 20-year risk of 8.3% for the development of breast cancer for formulations with daily progestogen (an increase of 1 in every 50 users) and 7.7% for formulations with intermittent progestogen (an increase of 1 in every 70 users). As for estrogen-only MHT, the absolute risk was 6.8% (an increase of 1 in every 200 users, with a greater excess in lean women).

“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,” said Joanne Kotsopoulos, PhD, of the Women’s College Research Institute, in a comment on the study.2 “For likely candidates, MHT (preferably [estrogen] alone) should be initiated around the time of natural menopause and ideally limited to 5 years of use.”

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1. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence [published online August 29, 2019]. Lancet. doi:10.1016/S0140-6736(19)31709-X

2. Kotsopoulos J. Menopausal hormones: definitive evidence for breast cancer [published online August 29, 2019]. Lancet. doi:10.1016/S0140-6736(19)31901-4