Hormone replacement therapy (HRT): further information on the known increased risk of breast cancer with HRT and its persistence after stopping

New data have confirmed that the risk of breast cancer is increased during use of all types of HRT, except vaginal estrogens, and have also shown that an excess risk of breast cancer persists for longer after stopping HRT than previously thought. Prescribers of HRT should discuss the updated total risk with women using HRT at their next routine appointment.

Advice for healthcare professionals:

  • a new meta-analysis of more than 100,000 women with breast cancer has shown that some excess risk of breast cancer with systemic HRT persists for more than 10 years after stopping; the total increased risk of breast cancer associated with HRT is therefore higher than previous estimates (see key findings)

  • prescribers of HRT should inform women who use or are considering starting HRT of the new information about breast cancer risk at their next routine appointment (see resources provided)

  • only prescribe HRT to relieve post-menopausal symptoms that are adversely affecting quality of life and regularly review patients using HRT to ensure it is used for the shortest time and at the lowest dose

  • remind current and past HRT users to be vigilant for signs of breast cancer and encourage them to attend for breast screening when invited

New study on the increased risk of breast cancer with HRT

Systemic hormone replacement therapy (HRT) is taken orally or applied under or via the skin (as gels or patches [transdermal]) for the relief of vasomotor or related symptoms of the menopause. For women with an intact uterus, progestogen is normally added to estrogen for the prevention of adverse endometrial effects such as hyperplasia and cancer.

On 29 August 2019, a new meta-analysis of participant data from the Collaborative Group on Hormonal Factors in Breast Cancer was published in The Lancet.1 The analysis included 108,647 cases of breast cancer in prospective studies. The study included long-term follow-up of women who did not use HRT and those who discontinued HRT, mostly in the early 2000s. Among women with complete information, mean HRT duration was 10 years in current users and 7 years in past users.

Key findings of the study are provided in this article. Prescribers are asked to discuss the new information on the risk of breast cancer with women using or contemplating using HRT at their next routine appointment. The MHRA has also sent this advice to healthcare professionals in an alert via the Central Alerting System.

Key findings:

  • All forms of systemic HRT are associated with a significant excess incidence of breast cancer, irrespective of the type of estrogen or progestogen or route of delivery (oral or transdermal)

  • There is little or no increase in risk with current or previous use of HRT for less than 1 year; however, there is an increased risk with HRT use for longer than 1 year

  • Risk of breast cancer increases further with longer duration of HRT use

  • Risk of breast cancer is lower after stopping HRT than it is during current use, but remains increased in ex-HRT users for more than 10 years compared with women who have never used HRT

  • Risk of breast cancer is higher for combined estrogen-progestogen HRT than estrogen-only HRT

  • For women who use HRT for similar durations, the total number of HRT-related breast cancers by age 69 years is similar whether HRT is started in her 40s or in her 50s

  • The study found no evidence of an effect on breast cancer risk with use of low doses of estrogen applied directly via the vagina to treat local symptoms

Estimates of number of extra cases of breast cancer for 5 years HRT use starting around the time of menopause

In the UK about 1 in 16 never-users of HRT (about 63 per 1000) will be diagnosed with breast cancer between the ages of 50 years and 69 years.

Among women of average weight who start using systemic HRT from menopause in their 40s or 50s, and continue for 5 years, the extra number of cases of breast cancer by age 69 years is estimated from the study1 to be:

  • around 1 extra case per 200 women (corresponding to about 5 extra cases per 1000 women) who use estrogen-only HRT
  • around 1 extra case per 70 women (corresponding to about 14 extra cases per 1000 women) who use estrogen combined with progestogen for part of each month (sequential or cyclical HRT)
  • around 1 extra case per 50 women (corresponding to about 20 extra cases per 1000 women) who use estrogen combined with daily progestogen HRT (continuous HRT)

The number of extra cases up to age 69 years is approximately double these values for women who use systemic HRT for 10 years compared with those who use HRT for 5 years.

A summary of the numbers of HRT-related breast cancers estimated from the new study, together with other risks and benefits of HRT use, is provided in table 1.

Effect on risk by type of HRT

All types of oral or transdermal HRT are associated with a significant excess incidence of breast cancer. The relative risk of breast cancer in women taking HRT is higher for combined estrogen-progestogen HRT than for estrogen-only HRT when compared with women who have never used HRT. The risks of breast cancer for women who use estrogen combined with progestogen for part of each month (sequential HRT) are slightly lower than with estrogen plus daily progestogen (continuous HRT). However, the risks are unaffected by the type of estrogen or progestogen, including progesterone itself, or the route by which HRT is administered (oral or transdermal routes).

The study found no evidence of an effect on breast cancer risk with use of estrogen applied directly via the vagina (via cream, tablet, or a ring) to treat local symptoms.1

Effect on risk by age of initiation of HRT

The risk of breast cancer depends on many factors, including age at menopause. Women who do not use HRT and who experience menopause between ages 40 and 50 years have a lower risk of breast cancer than women who experience menopause at a later age. However, in women who start HRT in their 40s, the number of HRT-related breast cancers diagnosed by age 69 years is similar to that in women who use HRT for a similar duration starting in their 50s. This is because women who have a menopause in their 40s have longer time as a current HRT-user plus ex-user before they are 69 years old.

It is not known if the increased risk of breast cancer with HRT use is similar for women who take HRT following a premature menopause (younger than age 40 years), or how their risk may be affected by any underlying conditions.

Effect on risk by duration of HRT use

Risk of breast cancer increases with duration of HRT use. For all types of HRT, relative risks of breast cancer are higher for women who use HRT for 5 or more years than for those who use it for 1–4 years of use. The number of extra cases of breast cancer up to age 69 years in women taking HRT is approximately doubled with 10 years of HRT use compared with use for 5 years (both for combined estrogen and progestogen HRTs and estrogen-only forms).

There appears to be little or no increase in risk of breast cancer for current or past users of HRT if it is used for less than 1 year.

Reminder for prescribers about licence recommendations for HRT

HRT should only be initiated for relief of postmenopausal symptoms that adversely affect quality of life and should be continued only as long as the benefit in alleviating menopause symptoms outweighs the risks associated with HRT use.

In all cases, a careful appraisal of all the risks and benefits should be undertaken before use. These should be reassessed regularly during use as a woman’s need for treatment and risk of adverse effects change over time.

A summary of the numbers of HRT-related breast cancers estimated from the new study,1 plus a summary other key risks and benefits of HRT use, is provided in table 1.

Table 2 provides revised estimates of relative and absolute risks of breast cancer per 1000 women with 5 or 10 years of HRT use from age 50 years from the new study. The table also provides a reminder of relative and absolute risks per 1000 women of other key risks and benefit in terms of reduction in fracture risk.

Counselling patients about the updated information on risk of breast cancer with HRT

Prescribers of HRT should discuss the updated risks of breast cancer with women using HRT at their next routine appointment.

What can an individual woman do to reduce her risk?

  • Using HRT for as short a time as possible will help reduce the overall risk

  • There are no medical risks with stopping HRT, but symptoms may return especially if HRT is stopped suddenly. Gradually stopping treatment may help to reduce the chances of this

  • Low-dose vaginal estrogens do not appear to increase breast cancer risk for women in whom this is a therapeutic option

The MHRA has produced an information sheet for women to assist healthcare professionals when providing counselling on the new information about risk of breast cancer with HRT (large-print version also provided). This sheet can be used in discussions with women about the risks of HRT. It is expected this sheet will be used by healthcare professionals alongside Table 1, which provides benefit and risk estimates for women for 5 years and 10 years use of HRT.

Patients should be encouraged to read the patient information leaflet (package leaflet) that accompanies their HRT since this provides information on other side effects and instructions for use.

Further information

Drug Safety Update. September 2007. Hormone-replacement therapy: updated advice.

This article has been published online on 30 August 2019, ahead of the next issue of Drug Safety Update, to enable healthcare professionals and patients to receive consistent information about risks with HRT.

Published 30 August 2019